STATEMENT OF PRIORITY

[0001] This application claims the benefit of U.S. Provisional Application Serial No.

62/429,668, filed December 2, 2016, the content of which is incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention is directed to compositions comprising an organ or tissue for transplantation and at least one chemorepellent agent for use in reducing or inhibiting transplantation rejection in subjects undergoing transplantation.

BACKGROUND OF THE INVENTION

[0003] Today, transplantation of organs, including heart, kidneys, liver, lungs, pancreas, intestine, skin, and thymus, as well as tissues such as bones, tendons (i.e., musculoskeletal grafts), cornea, heart valves, nerves and veins, is considered routine. As an example, skin grafts are used to repair skin damage such as damage from burns, trauma, disease (e.g., infection and/or cancer) and depigmentation (e.g., vitiligo). For a skin graft, a section of skin may be removed from one area of a person's body (autograft), removed from another human source (allograft), removed from another animal (xenograft), or artificially engineered and transplanted to the recipient site of a patient, e.g., a wound or infection site.

[0004] Complications associated with skin grafts and transplantation of other tissues and organs may include infection, graft failure and/or rejection of the skin graft, tissue and/or organ. Rejection of a transplanted organ or tissue may be lessened by using an autograft instead of an allograft or a xenograft. However, transplant rejection remains the leading impediment to long term transplant survival in humans and the ability to modulate the immune response of the transplant recipient may determine the success of surgical transplantation of organs and tissues.

[0005] There is a need in the art for improved methods for reducing transplant rejection.

SUMMARY OF THE INVENTION

[0006] One aspect of the invention relates to a transplantation composition comprising an organ or tissue for transplantation and a chemorepellent agent that repels effector T-cells. In some aspects, the chemorepellent agent may be a CXCR4 binding molecule and/or a CXCR7 binding molecule. [0007] Another aspect of the invention relates to a method for reducing immune rejection of an organ or tissue to be transplanted in a subject having a recipient site, the method comprising contacting the transplantation composition of the present invention to the recipient site.

[0008] These and other aspects of the invention are set forth in more detail in the description of the invention below.

BRIEF DESCRIPTION OF THE DRAWINGS

Figs. 1A-1D show dog tissues after 1 week post-transplantation. Figs. 1A-1B show the tissues from the mouse #1779 and Figs. 1C-1D show tissues from mouse #1778. Tissues without CXCL12 (SDF-la) in the left side of the body are shown in Figs. 1A and 1C and tissues coated with CXCL12 in the right side of the body are shown in Figs. IB and ID.

Figs. 2A-2D show dog tissues after 2 weeks post subcutaneous (S.C.) transplantation. 2A-2B show the dog tissues from mouse #1780 and Figs. 2C-2D show the dog tissues from mouse #1782. There were no tissues (without CXCL12) detectable at the left side of the body (Figs. 2A and 2C), and the tissues coated with CXCL12 are still visible and without obvious damage at this time point (Figs. 2B and 2D).

Figs. 3A-3F show transplanted dog tissues from mouse #1779 one week posttransplantation. The same dog tissue (IT-band) was cut in half before S.C. transplantation. The tissue part in the left side of the mouse (Figs. 3A-3C) was not coated with CXCL12. The tissue part in the right side (Figs. 3D-3F) was coated with CXCL12 at lug/ml concentration for 2 hours (haemotoxylin and eosin (H&E) staining).

Figs. 4A-4F shows transplanted dog tissues from the mouse #1778 one week posttransplantation. The same dog tissue (IT-band) was cut in half before S.C. transplantation. The tissue part in the left side of the mouse (Figs. 4A-4C) was not coated with CXCL12. The tissue part in the right side (Figs. 4D-4F) was coated with CXCL12at lug/ml concentration for 2 hours (H&E Staining).

Figs. 5A-5F shows transplanted dog tissues from mouse #1780 and #1782 two weeks post-transplantation. The same dog tissues (IT-band) were cut in half before S.C. transplantation. The tissue parts in the left side of the mice (Figs. 5A-5C) were not coated with CXCL12 and were not anymore present at this time point. The tissue

parts in the right side (Figs. 5D-5F) were coated with CXCL12 at lug/ml concentration for 2 hours. Tissue section from mouse #1780 is shown in (Figs. 5A-5C) and tissue section from chemorepellentmouse #1782 in (Figs. 5D-5F) (H&E Staining).

DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention now will be described hereinafter with reference to the accompanying drawings and examples, in which embodiments of the invention are shown. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. Thus, the invention contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention. Hence, the following descriptions are intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof.

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0011] All publications, patent applications, patents and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and/or paragraph in which the reference is presented.

[0012] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a composition comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0013] As used in the description of the invention and the appended claims, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0014] Also as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of

combinations when interpreted in the alternative ("or").

[0015] The term "about," as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1 % of the specified value as well as the specified value. For example, "about X" where X is the measurable value, is meant to include X as well as variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of X. A range provided herein for a measureable value may include any other range and/or individual value therein.

[0016] As used herein, phrases such as "between X and Y" and "between about X and Y" should be interpreted to include X and Y. As used herein, phrases such as "between about X and Y" mean "between about X and about Y" and phrases such as "from about X to Y" mean "from about X to about Y."

[0017] The terms "comprise," "comprises" and "comprising" as used herein, specify the presence of the stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

[0018] As used herein, the transitional phrase "consisting essentially of means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. Thus, the term "consisting essentially of when used in a claim of this invention is not intended to be interpreted to be equivalent to "comprising."

[0019] The terms "modulate," "modulates," or "modulation" refer to enhancement (e.g. , an increase) or inhibition (e.g., a decrease) in the specified level or activity.

[0020] The terms "enhance" or "increase" (and grammatical variations thereof) refer to an increase in the specified parameter of at least about 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-fold or an elevation of at least about 25%, 50%, 75%, 100%, 150%, 200%, 300%, 400%, 500% or more as compared to a control. [0021] As used herein, the terms "reduce," "inhibit," "diminish," and "decrease" (and grammatical variations thereof), describe, for example, a decrease or diminishment in the specified level or activity of at least about 5%, 10%, 15%, 20%, 25%, 35%, 50%, 75%, 80%, 85%, 90%), 95%), 97%, 98%, 99%, or 100% as compared to a control (e.g., reduced immune rejection of an organ or tissue transplant). In particular embodiments, the reduction may result in no or essentially no (i.e., at most an insignificant amount, e.g., less than about 10%) or even 5%>) detectable activity or amount.

[0022] The terms "contact" or "apply" (or grammatical variations thereof) as used herein refers to placing the components of a desired reaction together under conditions suitable for carrying out the desired reaction (e.g., creating a stable transplantation between an

organ/tissue and a recipient site and/or preparing an organ or tissue for transplantation and/or recipient site for transplantation). Thus, with respect to an organ or tissue and a recipient site, apply or contact refers to bringing the organ or tissue for transplanting and the recipient site in sufficiently close proximity to each other to allow the organ or tissue to adhere or be attached to the recipient site. With respect to an organ/tissue and agents and/or a recipient site and agents (e.g., chemorepellent, an antimicrobial agent, silver ions, a protease inhibitor, and/or an extracellular matrix molecule), these terms refer to placing an organ/tissue to be transplanted and/or a recipient site and one or more agents together under conditions suitable to prepare the organ/tissue and/or the recipient site for the transplantation process and for reducing the likelihood of rejection of the organ or tissue.

[0023] A "patient" or "subject" as used interchangeably herein refers to any mammal in need of an organ or tissue transplantation. A mammal may be human or non-human mammal. A mammalian subject may be, for example, a laboratory animal (e.g., a rat, mouse, guinea pig, rabbit, primate, etc.), a farm or commercial animal (e.g., a cow, horse, goat, donkey, sheep, etc.), or a domestic animal (e.g., cat, dog, ferret, etc.). In some embodiments, a subject may be a primate subject, a non-human primate subject (e.g., a chimpanzee, baboon, monkey, gorilla, etc.) or a human. Suitable subjects include both males and females and subjects of any age, including embryonic (e.g., in utero or in ovo), infant, juvenile, adolescent, adult and geriatric subjects.

[0024] By "chemorepellent activity" or "chemorepellant effect" it is meant the ability of an agent to repel (or chemorepel) a eukaryotic cell with migratory capacity (i.e., a cell that can move away from a repellant stimulus), as well as the chemorepellent effect of a chemokine secreted by a cell, e.g., a tumor cell. Usually, the chemorepellent effect is present in an area around the cell wherein the concentration of the chemokine is sufficient to provide the chemorepellent effect. Some chemokines, including interleukin 8 and CXCL12, may exert chemorepellent activity at high concentrations (e.g., over about 100 nM), whereas lower concentrations exhibit no chemorepellent effect and may even be chemoattractant. Thus, in some embodiments, a chemorepellent agent useful with the present invention is present in the composition or applied to an organ or tissue to be transplanted or a recipient site at a concentration of at least 100 nM.

[0025] Accordingly, an agent with chemorepellent activity is a "chemorepellent agent." Chemorepellent agents are agents that have migratory cell (e.g., immune cell) repellent activity (i.e., chemorepellent effect). Chemorepellent agents (e.g., CXCL12 and other CXCR4- or CXCR7-binding molecules) can repel and modify the function of effector T-cells while recruiting immune-suppressive regulatory T-cells to a transplantation site on a subject. This action allows for a down-regulation of immune activity in, for example, a localized area. Such activity can be detected using any of a variety of systems well known in the art (see, e.g., U.S. Pat. No. 5,514,555 and U.S. Patent Application Pub. No. 2008/0300165, each of which is incorporated by reference herein in its entirety). A preferred system for use herein is described in US Patent 6,448,054, which is incorporated herein by reference in its entirety. Without being bound by theory, it is believed that chemorepellent agents may inhibit or attenuate an immune response at a transplantation or recipient site of a transplantation in a subject, thereby improving the likelihood of success of implantation of the organ or tissue.

[0026] The term "allogeneic" means belonging to or obtained from the same species.

[0027] The term "xenogeneic" means belonging to or obtained from a different species.

[0028] The term "effector T-cell" refers to a differentiated T-cell capable of mounting a specific immune response by releasing cytokines.

[0029] The term "regulatory T-cell" refers to a T-cell that reduces or suppresses the immune response of B-cells or of other T-cells to an antigen

[0030] The term "effective amount" refers to that amount of a compound, material, or composition which is sufficient to effect a desired result. An effective amount of a compound can be administered in one or more administrations.

[0031] A "therapeutically effective" amount as used herein is an amount that provides some improvement or benefit to the subject (e.g., reduce an immune rejection of an organ or tissue that is implanted on a recipient site of a subject).

[0032] A "prophylactically effective" amount as used herein is an amount that is sufficient to prevent and/or delay the onset of a disease, disorder and/or clinical symptoms in a subject and/or to reduce and/or delay the severity of the onset of a disease, disorder and/or clinical symptoms in a subject relative to what would occur in the absence of the methods of the invention (e.g., prevent or delay an immune rejection of a transplanted organ or tissue).

Those skilled in the art will appreciate that the level of prevention need not be complete, as long as some benefit is provided to the subject.

[0033] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0034] A "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically- acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and/or (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0035] A "pharmaceutically-acceptable salt" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds.

[0036] The term "immunogenic" refers to the ability of a substance to elicit an immune response. An "immunogenic composition" or "immunogenic substance" is a composition or substance which elicits an immune response.

[0037] As used herein, "immune response" refers to a response made by the immune system of an organism to a substance, which includes but is not limited to foreign or self-proteins. There are three general types of "immune response" including, but not limited to mucosal, humoral and cellular "immune responses." An "immune response" may include at least one of the following: antibody production, inflammation, developing immunity, developing hypersensitivity to an antigen, the response of antigen specific lymphocytes to antigen, tolerance, and transplant or graft rejection.

[0038] An "immune response" may be measured using techniques known to those of skill in the art. For example, serum, blood or other secretions may be obtained from an organism for which an "immune response" is suspected to be present, and assayed for the presence of immunoglobulins using an enzyme-linked immuno-absorbant assay (ELISA; U.S. Pat. No. 5,951,988; Ausubel et al., Short Protocols in Molecular Biology 3.sup.rd Ed. John Wiley & Sons, Inc. 1995). A statistical test known in the art may be used to determine the difference in measured immunoglobulin levels including, but not limited to ANOVA, Student's T-test, and the like, wherein the P value is at least <0.1, <0.05, <0.01, <0.005, 0.001, and even O.0001.

[0039] In general, an "immune response" may be measured using other techniques such as immunohistochemistry using labeled antibodies which are specific for portions of the immunoglobulins raised during the "immune response." Microscopic data obtained by immunohistochemistry may be quantitated by scanning the immunohistochemically stained tissue sample and quantitating the level of staining using a computer software program known to those of skill in the art including, but not limited to ΝΓΗ Image (National Institutes of Health, Bethesda, Md.). According to the present invention, a composition of the present invention comprising an organ or tissue for transplantation and a chemorepellent agent can be said to reduce an "immune response" in a subject if the quantitative measure of immunohistochemical staining in the subject receiving the composition is statistically different from the measure of immunohistochemical staining detected in a subject not receiving the composition (e.g., receiving an organ or tissue transplantation but without a chemorepellent agent). A statistical test known in the art may be used to determine the difference in measured immunohistochemical staining levels including, but not limited to ANOVA, Student's T-test, and the like, wherein the P value is at least <0.1, <0.05, <0.01, <0.005, O.001, and even O.0001.

[0040] Thus, if a patient is mounting a humoral immune response to the antigen, anti-antigen antibody titer may be measured. A typical immunoassay consists of coating the wells of an immunoassay plate with the antigen (for example by adding recombinant antigen or using a capture anti-antigen antibody) and then adding serial dilutions of patient serum to the wells, After washing away the sera, human immunoglobulins are detected with a conjugated anti- human immunoglobulin. [00 1] A cellular immune response may be measured by using a cell-killing assay. In one example, a subject's peripheral blood lymphocytes (PBL) are isolated and added at different ratios to a CHO cell line expressing the antigen (non-transfected CHO cells or CHO cells transfected with a non-antigen construct are used as negative control). The antigen expressing CHO cells are transfected with an antigen construct and selected to express antigen on their surface. Killing is measured using radioactivity or release of a specific dye. A cellular response may also be measured by detecting the presence or amount of specific immune cell types, e.g., using flow cytometry.

[0042] The present invention takes advantage of the biological activities of chemorepellent agents that repel effector T-cells such as CXCL12 and CXCL12 derivatives in activating or inhibiting immune responses associated with the CXCR4 and/or CXCR7 pathways. By providing a composition comprising an organ or tissue and a chemorepellent agent to a recipient site in a subject, e.g., anatomical site, surgical site, a wound, an infection, etc., the compositions of the invention can be used advantageously to provide localized modulation of the immune response in a subject, thereby reducing an immune rejection of an organ or tissue transplanted in a subject.

[0043] Current technologies protect implanted cells, tissues, organs or devices from destruction by the immune or inflammatory response in a time limited manner. Incorporation of chemorepellent agents that repel effector T-cells such as CXCL12 results in long term self- sustaining support for the implanted tissue or organ by inducing supportive production of the chemorepellent agent from the tissue. In other words, the chemorepellent agent in the transplant composition of the invention initiates an extended production of supportive endogenous anti-inflammatory/ anti-immune cytokines that support the implanted tissue and/or organ over the long term and creates a self-sustaining protection of the transplanted tissue and/or organ.

[0044] Thus, the present invention relates to compositions comprising an organ or tissue for transplantation and a chemorepellent agent and the use of such compositions for reducing immune rejection of an organ or tissue that is transplanted or implanted on a subject having a recipient site. This disclosure is predicated on the discovery that chemorepellent agents (e.g., CXCL12 and other CXCR4- or CXCR7-binding molecules) can reduce or prevent the occurrence of an immunological response directed against a transplanted organ or tissue.

[0045] In some embodiments, the present invention provides a composition comprising an organ or tissue and a chemorepellent agent that repels effector T-cells. In some embodiments, an organ or tissue may be coated over its entire surface, or a portion thereof, with a chemorepellent agent.

[0046] In some embodiments, the organ or tissue is skin (e.g., a skin graft), and "a portion" of the skin means some or all of the dermal side of the skin (the side of the skin to be placed adjacent to the recipient site and which adheres to the recipient site). Thus, in some embodiments, only the dermal side of a skin graft may be coated with a chemorepellent agent.

[0047] In some embodiments, a composition may comprise an organ or tissue that has been in the presence of (e.g., coated with) at least one chemorepellent agent for at least one day (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days) prior to applying (e.g., implanting, transplanting) the composition to a recipient site on a subject. In some embodiments, the composition comprises an organ or tissue that has been in the presence of at least one chemorepellent agent for at least one week (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 weeks) prior to applying the composition to a recipient site on a subject.

[0048] In some embodiments, a chemorepellent agent of a composition of the present invention may be any agent that repels effector T-cells. In some embodiments, a

chemorepellent agent of a composition of the present invention may be at least one (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) CXCR4 binding molecule and/or CXCR7 binding molecule and/or any combination thereof. In some embodiments, a CXCR4 binding molecule and/or CXCR7 binding molecule may include, but is not limited to, CXCL12, CXCL12 polypeptides (e.g., CXCL12 isoforms or modified sequences; peptide (e.g., a variant of CXCL12 having at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% of the activating activity of wild type CXCL12), CXCL12 derived chemorepellent peptides, an antibody to CXCR4, an antibody to CXCR7, or any other ligand (e.g., agonist) for CXCR4 or CXCR7. In some embodiments, a chemorepellent agent may be IL-8 or CXCL12 (also called SDF-1), or a chemorepellent active fragment thereof or a homologue of a fragment thereof. In some embodiments, a chemorepellent agent may be CXCL12. In one embodiment, a CXCL12 polypeptide is a biologically active fragment or analog of a wild-type CXCL12 polypeptide.

[0049] Thus, a CXCL12 polypeptide useful with this invention may be any CXCL12 polypeptide that activates the CXCL12/CXCR4 and/or CXCL12/CXCR7 pathway.

Activators of the CXCL12/CXCR4 and/or CXCL12/CXCR7 pathway useful with the invention may include, but are not limited to, wild-type CXCL12 or CXCL12 mutants, fusion proteins/genes, truncations and/or analogues. In some embodiments, the CXCL12 polypeptide is wild-type CXCL12 (e.g., mammalian CXCL12, e.g., human CXCL12) or an active fragment thereof, e.g. , a CXCL12 polypeptide containing a N-terminal and/or C- terminal truncation and/or internal deletion. Non-limiting examples of CXCL12 truncation variants that can activate CXCR4 or CXCR7 include CXCL12[22-89] and CXCL12[22-88] (Richter et al. Stem Cells Dev. 23(16):1959-1974 (2014)). In some embodiments, the CXCL12 polypeptide is one having one or more mutations (e.g., additions, deletions, and/or substitutions) that retains at least a portion of the biological activity of wild-type CXCL12 (e.g., at least about 20, 30, 40, 50, 60, 70, 80, 90, 95% of wild type). Non-limiting examples of CXCL12 mutants that may be useful as activators of CXCR4 include S-SDF-1(S4V) (Segers et al. C/rcw/ t cw: 116(5): 1683-1692 (2007) and Segers et al. Circulation 123:1306- 1315 (2011)) and AAV-[S4V]-SDF-l and V-[S4V]-SDF-la (Baumann et al. J Controlled Release 162:68-75 (2012)). Non-limiting examples of CXCL12 fusion proteins/genes that may be useful as activators of CXCL4 or CXCR7 include CXCL12-GL (CXCL12 fused to Gaussia luciferase) (Luker et al. Biotechniques 47(l):625-632 (2009)), SDF1-GPVI protein (SDF-1 -glycoprotein VI)(Ziegler et al. Circulation 125(5):685-696 (2012)), SDF-1/HOXB4 (Chen et al. Am. J. Transl. i¾s.6(6):691-702 (2014)), S1FG (SDF-1/CXCL12 fused to fractalkine mucin stalk and GPI anchor from LFA-3) (Stachel et al. Stem Cells 31 :1795-1805 (2013)), and affinity tagged CXCL12 (e.g., CXCL12-Strep) (Picciocchi et al. PLoS One 9(l):e87394 (2014)). Non-limiting examples of CXCL12 analogues that may be useful as activators of CXCR4 or CXCR7 include lactam analogues of CXCL12, CTCE 0021 and CTCE 0214 (Patrussi et al. Curr. Med. Chem. 18:497-512 (2011)), HSEFFR-CPC-RFFESH (SDF-1 {H-H}) (Palladino et al. FEBS Letters 579:5293-5298 (2005)), and SDF-1 analogue (N33A) (Ueda et al. J. Biol. Chem. 272(4) :24966-24970 (1997)). Additional examples of modified CXCL12 sequences for activation of the CXCL12/CXCR4 and/or

CXCL12/CXCR7 pathway include, without limitation, sequences disclosed in US Patent Nos. 7,696,309 (protease resistant sequences); 7,999,067 (protease resistant sequences); 9,308,277 (protease resistant sequences); 9,631,005 (protease resistant sequences); 7,776,564 (splice variants); 8,058,403 (splice variants); 7,923,016 (locked dimers); 8,524,670 (locked dimers); and 9,346,871 (locked dimers), each of which are incorporated by reference herein for the disclosed sequences.

[0050] Thus, a CXCL12 polypeptide sequence useful with the invention may be any isoform of CXCL12. CXCL12 polypeptides are known in the art. See, for example, Poznansky et al., Nature Medicine 2000, 6:543-8. Note that the terms CXCL12 and SDF-1 may be used interchangeably. Exemplary CXCL12 isoforms are provided in Table 1. In one embodiment, a CXCL12 polypeptide has at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or 100% amino acid sequence identity to any one of the isoforms listed in Table 1. When the chemorepellent agent of the invention comprises more than one CXCL12 polypeptide sequence, the sequences may be the same isoform (e.g., two CXCL12- α isoforms) or different isoforms.

Table 1. CXCL12 isoforms

Name Accession Accession Number Sequence SEQ ID NO.

Number Versions

CXCL12 Yu et al. MNAKVVVVLV SEQ ID NO:4

Delta Identification and LVLTALCLSD

expression of GKPVSLSYRC

novel isoforms of PCRFFESHVA

human stromal RANVKHLKIL

cell-derived factor NTPNCALQIV

1. Gene (2006) ARLKNNNRQV

vol. 374 pp. 174-9 CIDPKLKWIQ

EYLEKALNNL

ISAAPAGKRV

IAGARALHPS

PPRACPTARA

LCEIRLWPPP

EWSWPSPGDV

CXCL12 Yu et al. MNAKVVVVLV SEQ ID NO:5

Epsilon Identification and LVLTALCLSD

expression of GKPVSLSYRC

novel isoforms of PCRFFESHVA

human stromal RANVKHLKIL

cell-derived factor NTPNCALQIV

1. Gene (2006) ARLKNNNRQV

vol. 374 pp. 174-9 CIDPKLKWIQ

EYLEKALNNC

CXCL12 Yu et al. MNAKVVVVLV SEQ ID NO:6

Phi Identification and LVLTALCLSD

expression of GKPVSLSYRC

novel isoforms of PCRFFESHVA

human stromal RANVKHLKIL

cell-derived factor NTPNCALQIV

1. Gene (2006) ARLKNNNRQV

vol. 374 pp. 174-9 CIDPKLKWIQ

EYLEKALNKI

WLYGNAETSR

[0051] In some embodiments, 1 to 5 of the first consecutive amino acid residues of the CXCL12 polypeptide sequence are deleted relative to the wild-type CXCL12 sequence. Reference to the first five consecutive amino acid residues of the CXCL12 polypeptide sequence refers to the sequence KPVSL in mature human CXCL12 and the corresponding residues from CXCL12 of other species. In some embodiments, 1, 2, 3, 4, or 5 of the first consecutive amino acid residues of the CXCL12 polypeptide sequence are deleted. In some embodiments, the recombinant CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 7.

MNA VVVVLVLVLTALCLSDGSYRCPCRFFESHVAPvANVKHLKILNTPNCALQIVA RLKNN RQVCIDPKLKWIQEYLEKALNK (SEQ ID NO:7)

[0052] In some embodiments, the sixth amino acid residue of the CXCL12 polypeptide sequence is substituted relative to the wild-type CXCL12 sequence. The sixth amino acid residue in human CXCL12 is a serine. The residue may be substituted with a conservative substitution. In some embodiments, the residue is substituted with alanine. In some embodiments, the recombinant CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 8.

MNAKVVVVLVLVLTALCLSDGKPVSLAYRCPCRFFESHVARANVKHLKILNTPNCA LQIVARLKNNNRQVCIDPKLKWIQEYLEKALNK (SEQ ID NO: 8)

[0053] In some embodiments, the deletion of 1 to 5 of the first consecutive amino acid residues of the CXCL12 polypeptide sequence is combined with the substitution of the sixth residue. Thus, the modified CXCL12 polypeptide may have 1, 2, 3, 4, or 5 of the first consecutive amino acid residues deleted in combination with substitution of the sixth residue, e.g., to alanine. In some embodiments, the CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:9.

MNAKVVVVLVLVLTALCLSDGAYRCPCRFFESHVARANVKHLKILNTPNCALQIVA RLKNNNRQVCIDPKLKWIQEYLEKALNK (SEQ ID NO:9)

In one embodiment, the CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 10.

SYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQVCIDPKLKWIQEYL EKALN

K (SEQ ID NO: 10) [0054] In some embodiments, the CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 11.

AYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNN RQVCIDPKLKWIQEYLEKALN

(SEQ ID NO: 11)

[0055] In some embodiments, the CXCL12 polypeptide comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 12.

KPVSLAYRCPCRFFESHVARANVKHLKILNTPNCALQIVARLKNNNRQVCIDPKLKW IQEYLEKALNK (SEQ ID NO: 12)

[0056] Conservative amino acid substitutions in the CXCL12 polypeptides of the invention may be based on any characteristic known in the art, including the relative similarity or differences of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like.

[0057] In identifying amino acid sequences encoding polypeptides other than those specifically disclosed herein, the hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art {see, Kyte and Doolittle, J. Mol. Biol. 157: 105 (1982); incorporated herein by reference in its entirety). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like.

[0058] Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics (Kyte and Doolittle, id.), these are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5);

methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (- 0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5);

aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

[0059] Accordingly, the hydropathic index of the amino acid (or amino acid sequence) may be considered when modifying the peptides specifically disclosed herein for use as a chemorepellent agent. [0060] It is also understood in the art that the substitution of amino acids can be made on the basis of hydrophilicity. U.S. Patent No. 4,554,101 (incorporated herein by reference in its entirety) states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein.

[0061] As detailed in U.S. Patent No. 4,554, 101, the following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (±3.0); aspartate (+3.0 ± 1); glutamate (+3.0 ± 1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0);

threonine (-0.4); proline (-0.5 ± I); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4).

[0062] Thus, the hydrophilicity of the amino acid (or amino acid sequence) may be considered when identifying additional peptides beyond those specifically disclosed herein.

[0063] Additional chemorepellent agents are described, for example, in U.S. Patent No. 6,448,054, which is incorporated herein by reference for the teachings relevant to

chemorepellent agents as disclosed therein.

[0064] In some embodiments, composition of the invention may be made by contacting, applying, and/or coating an organ or tissue for transplantation with a composition comprising at least 50 nM (e.g., 50,100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 650, 700, 750, 800, 850, 900, 950, 1000, 1 100, 1200, 1300, 1400, 1500 nM or more of a chemorepellent agent)

[0065] In some embodiments, a composition of the invention may be made by contacting, applying, or coating the organ or tissue with a composition comprising about 500 ng/mL to about 5 μg/mL of a chemorepellent agent. Thus, in some embodiments, a chemorepellent agent may be present in a composition at a concentration of about 500 ng/mL to about 5 μg/mL (e.g. , about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000 ng/mL). In some embodiments, a chemorepellent agent may applied to an organ or tissue in an amount to deliver to the organ or tissue about 500 nanograms per milliliter per day (ng/mL/day) to about 5 micrograms/mL/day

^g/mL/day) of the chemorepellent agent (e.g., about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000 ng/mL/day). [0066] In some embodiments, the chemorepellent agent provides a chemorepellent environment for an organ or tissue for transplantation at a recipient site for at least four weeks (e.g., about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 3 months, 4 months, 5 months, 6 months or more) after implantation.

[0067] In some embodiments, the chemorepellent agent may be encapsulated in and/or coated on particles (e.g., nanoparticles, microcapsules, macrocapsules) comprising a biocompatible and biodegradable polymer. In some embodiments, a biocompatible and biodegradable polymer of a particle for encapsulating a chemorepellent agent may be a natural polymer or a synthetic polymer. A natural polymer useful for a particle for encapsulating a chemorepellent agent can include, but is not limited to, fibrin, collagen, chitosan, gelatin, alginate, or hyaluronan, or any combination thereof. A synthetic polymer useful for a particle for encapsulating a chemorepellent agent can include, but is not limited to, poly(lactic acid) (PLA), poly(glycolic) acid (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(caprolactone) (PCL), polyorthoester, poly(dioxanone), poly(anhydride),

poly(trimethylene carbonate), or polyphosphazene, or any combination thereof. In some embodiments, particles for encapsulating a chemorepellent agent may have an average diameter of about 5 nanometers to about 500 nanometers.

[0068] In some embodiments, the particles may be configured to release over time a chemorepellent agent in an amount effective for providing a chemorepellent environment for an organ or tissue for transplantation at a recipient site for at least four weeks (e.g., about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 3 months, 4 months, 5 months, 6 months or more) after implantation. In some embodiments, the chemorepellent agent is released by the particles at a rate of at least about 1 femtomol per minute (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 femtomol or more per minute).

[0069] In some embodiments, in addition to a chemorepellent agent, a particle may comprise a pharmaceutically acceptable excipient. Acceptable excipients are nontoxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such an excipient may be any solid, liquid, semisolid or gaseous excipient that is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.

Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 22nd ed., 2013).

[0070] In some embodiments, the particles encapsulating the chemorepellent agent may comprise magnetic beads. The magnetic beads may be used to facilitate the removal of the particles (nanoparticles, microcapsules, macrocapsules) from the in vivo setting - in the context of, for example, intraperitoneal transplantation, subcutaneous implantation or implantation at other anatomic sites. No alternative approach currently exists to remove such particles from an anatomic site.

0041] In some embodiments, a transplantation composition of the present invention may further comprise an organ or tissue coated (e.g., over the entire surface or on a portion of the organ or tissue (e.g., only the dermal side of a skin graft) with an antimicrobial agent or silver ions. Thus, in some embodiments, a composition of the invention may comprise one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) antimicrobial agents. Thus, a surface of an organ or tissue may be contacted with (e.g., sprayed, infused, etc.) at least one antimicrobial agent prior to, concurrently with, or after contacting the surface of the organ or tissue with a chemorepellent agent. Example antimicrobial agents include, but are not limited to, nitrofurazone, silver sulfadiazine, povidone-iodine, silver nitrate (Ag), neomycin, bacitracin, Ringer's lactate (RL), gentamicin, triple antibiotic, cephalothin, cephalexin, cephazolin, cephalosporin, clindamycin, nafcillin, quinolones, macrolides, vancomycin, mupirocin, or any combination thereof. In some embodiments, an organ or tissue composition of the invention may comprise silver ions (Ag). Those of skill in the art are capable of determining the amount of an antimicrobial agent or silver ions necessary for conferring a benefit (e.g., an antimicrobial effect) to the organ or tissue and the subject having the recipient site for receiving the organ or tissue.

[0071] In some embodiments, a transplantation composition of the present invention may comprise an organ or tissue coated (e.g., over the entire surface or a portion thereof (e.g., on the dermal side of a skin graft)) with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) protease inhibitors. Thus, the surface of an organ or tissue (entire surface or portion thereof) may be contacted with (e.g., sprayed, infused, etc.) at least one protease inhibitor prior to or concurrently with contacting the surface (entire surface or portion thereof) of the organ or tissue with a chemorepellent agent. Accordingly, in some embodiments, an organ or tissue may be contacted with at least one protease inhibitor prior to or concurrently with contacting the organ or tissue with a chemorepellent agent. Those of skill in the art are capable of determining the amount of a protease inhibitor necessary for conferring a benefit to the organ or tissue to be transplanted and the subject having the recipient site for receiving the organ or tissue.

[0072] In some embodiments, a composition of the present invention may comprise an organ or tissue coated (e.g., over the entire surface or a portion thereof (e.g., on the dermal side of a skin graft)) with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) extracellular matrix molecules. Thus, for example, an organ or tissue (entire surface or portion thereof) may be contacted with (e.g., sprayed, infused, etc.) an extracellular matrix molecule prior to, concurrently with or after being contacted with a chemorepellent agent. Without being limited to any particular theory, an extracellular matrix molecule may bind to the surface of the organ or tissue and to the chemorepellent agent, thereby binding the chemorepellent agent to the organ or tissue. Example extracellular matrix molecules include, but are not limited to, fibronectin, laminin, collagen, integrin, cadherin, selectin, hyaluronic acid, and/or a proteoglycan (e.g., heparan sulfate, keratan sulfate, chondroitin sulfate). Those of skill in the art are capable of determining the amount of an extracellular matrix molecule necessary for conferring a benefit (e.g., adherence of the chemorepellent agent to the organ or tissue for transplantation) to an organ or tissue for transplantation and the subject having a recipient site for receiving the organ or tissue for transplantation.

[0073] An organ or tissue may be coated (over its entirety or a portion thereof (e.g., the dermal side of skin for transplantation)) with an agent (e.g., a chemorepellent agent, an antimicrobial agent, a protease inhibitor, silver ions, extracellular matrix molecule) or any other compound or composition of interest in any manner and in any combination. For example, coating an organ or tissue may comprise spraying or infusing the agent/compound of interest onto the organ or tissue.

[0074] In some embodiments, a composition of the invention comprises an autologous organ or tissue (from the subject's own body), an isogeneic organ or tissue (not from the intended recipient but from a genetically identical individual), an allogenic organ or tissue (from a different individual than the intended recipient but the same species), a xenogenic organ or tissue (from a different species), or an engineered organ or tissue (from tissue generated in a laboratory, e.g., artificial).

[0075] In some embodiments, an organ may be any organ that may be transplanted including, but not limited to, a heart, a kidney, a liver, a lung, a bladder, a ureter, a stomach, an intestine (small and large), skin, a tongue, an esophagus, an endocrine gland (e.g., pancreas, adrenal gland, salivary gland, thyroid gland, pituitary gland, etc.), bone marrow, a spleen, a thymus, a lymph node, a tendon, a ligament, a muscle, a uterus, a vagina, an ovary, a fallopian tube, a penis, a cornea, a lens, a retina, a middle ear, an outer ear, a cochlea, an iris, a vein, and the like.

[0076] Example tissues useful with this invention include any tissue that may be transplanted including, but not limited to, a bone, cartilage, tendon, ligament, cornea, heart valve, nerve and/or vein, middle ear, and/or cultured tissue (for example, differentiated cells that may function as an organ or a tissue), 3D engineered tissues.

[0077] Tissues/cells/organs useful with this invention may be human and/or non-human, for example, porcine or other xenogeneic tissues.

[0078] In another aspect, methods for use of the composition of the invention are provided. Thus, in some embodiments, a method for reducing immune rejection of an organ or tissue to be implanted in a subject having a recipient site is provided, the method comprising applying a transplantation composition of the invention to the recipient site. In some embodiments, a recipient site may be prepared prior to contacting the transplantation composition of the invention to the recipient site.

[0079] In some embodiments, a method for reducing immune rejection of an organ or tissue to be transplanted in a subject having a recipient site is provided, the method comprising contacting the recipient site with a chemorepellent agent. In some embodiments, the recipient site is contacted with the chemorepellent agent before, at the same time

(concurrently with), or after transplantation of an organ or tissue into the subject. In some embodiments, prior to transplantation, an organ or tissue to be transplanted may be contacted with a chemorepellent agent (e.g., a composition of the invention comprising an organ or tissue and a chemorepellent agent that repels effector T-cells). In some embodiments, a tissue or an organ is not contacted with a chemorepellent agent prior to transplantation.

[0080] In some embodiments, a recipient site may be a site of an organ or tissue that is to be replaced, an anatomical site, a surgical site, a lymph node, an abrasion, a burn, an incision, a laceration, a post-surgical wound, an ulcer (e.g., a diabetic ulcer of the leg and/or foot, a pressure sore, a bed sore, vascular disease (e.g., peripheral vascular disease), an amputation, an avulsion, an infection, or a depigmentation disease (vitiligo), or any combination thereof.

[0081] In some embodiments, preparing a recipient site for receiving a composition of the invention or contacting a recipient site with a chemorepellent agent may comprise applying an effective amount of at least one chemorepellent agent that repels effector T-cells to the recipient site prior to contacting with a composition of the invention or prior to, at the same time or after implantation or an organ or tissue. In some embodiments, applying an effective amount of a chemorepellent agent to a recipient site may comprise spraying at least one layer of an effective amount of the chemorepellent agent on the recipient site of the subject. In some embodiments, applying an effective amount of a chemorepellent agent to a recipient site may comprise infusing an effective amount of a chemorepellent agent into a recipient site of the subject. As used herein, "at least one layer" means spraying the whole of the surface of a recipient site with the chemorepellent agent, thereby coating the surface of the recipient site at least one time. "More than one layer" of an effective amount of the chemorepellent agent means that the recipient site's surface is coated at least two times (e.g., 2, 3, 4, 5, 6, 7, or more times) with the chemorepellent agent. In some embodiments, when more than one layer is applied, the chemorepellant is dried between applications. Any method of drying useful with the particular recipient site may be used.

[0082] In some embodiments, preparing a recipient site for receiving a composition of the invention or contacting a recipient site with a chemorepellent agent may comprise applying an effective amount of at least one chemorepellent agent encapsulated in and/or coated on particles (e.g., nanoparticles, microcapsules, macrocapsules) comprising a biocompatible and biodegradable polymer as described herein.

[0083] A chemorepellent agent useful for contacting a recipient site or for preparing a recipient site for transplantation of an organ or tissue may be any chemorepellent that repels effector T-cells as described herein for use with the transplantation composition (e.g., a CXCR4 binding molecule and/or a CXCR7 binding molecule, or any combination thereof).

[0084] In some embodiments, an effective amount of a chemorepellent agent for application to a recipient site may be an amount that provides a local concentration of the chemorepellent agent of 100 nM or more. In some embodiments, the concentration of a composition of a chemorepellent agent for application to a recipient site may be about 500 ng/mL to about 5 μg/mL. Thus, in some embodiments, an effective amount of a chemorepellent agent applied to a recipient site may be about 500 ng/mL to about 5 μg/mL (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000 ng/mL). In some embodiments, a chemorepellent agent may be applied to a recipient site in an amount so as to deliver about 500 nanograms per milliliter per day (ng/mL/day) to about 5 micrograms/mL/day ^g/mL/day) of the chemorepellent agent to the environment in and around the recipient site (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000 ng/mL/day).

[0085] In some embodiments, a chemorepellent agent may be in the form of, for example, a cream, a lotion, an ointment, a gel, a solution, a spray, or a foam that can be incorporated into a composition with an organ or tissue and/or applied to and organ or tissue and/or to a recipient site. In some embodiments, particles comprising a chemorepellent agent may be in the form of, for example, a cream, a lotion, an ointment, a gel, a solution, a spray, or a foam that can be incorporated into a composition with an organ or tissue and/or applied to an organ or tissue and/or to a recipient site.

[0086] In some embodiments, contacting a recipient site or preparing a recipient site may further comprise applying at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) antimicrobial agent to the recipient site of the subject. Thus, a recipient site may be contacted with (e.g., sprayed, infused, etc.) at least one antimicrobial agent prior to, concurrently with, or after contacting the recipient site with a composition of the invention (e.g., a tissue/organ and chemorepellent agent). In some embodiments, preparing a recipient site may comprise applying silver ions to a recipient site of a subject. Example antimicrobial agents include, but are not limited to, nitrofurazone, silver sulfadiazine, povidone-iodine, silver nitrate (Ag), neomycin, bacitracin, Ringer's lactate (RL), gentamicin, triple antibiotic, cephalothin, cephalexin, cephazolin, cephalosporin, clindamycin, nafcillin or mupirocin or any

combination thereof. Those of skill in the art are capable of determining the amount of an antimicrobial agent or silver ions necessary for conferring a benefit (e.g., an antimicrobial effect) to implantation of an organ or a tissue and the subject having the recipient site for receiving the organ or tissue.

[0087] In some embodiments, contacting a recipient site with a chemorepellent agent or preparing a recipient site for receiving a composition of the invention may comprise applying at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) extracellular matrix molecule to the recipient site. Thus, for example, an extracellular matrix molecule may be applied (e.g., sprayed, infused, etc.) to a recipient site prior to or concurrently with contacting the recipient site with a tissue or organ for transplantation or with a composition of the invention (e.g., a tissue/organ and chemorepellent agent). In some embodiments, an extracellular matrix molecule may be applied to a recipient site prior to applying a chemorepellent agent to the recipient site and prior to contacting the recipient site with an organ or tissue or with a composition of the invention. Example extracellular matrix molecules include, but are not limited to, fibronectin, laminin, collagen, integrin, cadherin, selectin, hyaluronic acid, and/or a proteoglycan (e.g., heparan sulfate, keratan sulfate, chondroitin sulfate). Those of skill in the art are capable of determining an amount of an extracellular matrix molecule necessary for conferring a benefit (e.g., adherence of the chemorepellent agent to the recipient site) to the implantation of an organ or a tissue and the subject having a recipient site for receiving the organ and/or tissue.

[0088] In further embodiments, a method of reducing rejection of a transplanted organ or tissue in a subject is provided, the method comprising administering to the subject an effective amount of a chemorepellent agent, thereby reducing the rejection of the transplanted organ or tissue in the subject. In some embodiments, the chemorepellent agent may be in composition comprising a pharmaceutically acceptable carrier.

[0089] In some embodiments, a chemorepellent agent may be systemically administered to a subject. The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. "Parenteral administration" and "administered parenterally" means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intralesional, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injection, oral, epidural, intranasal and infusion. In some embodiments, the composition comprising a chemorepellent may be administered to a subject prior to, during or after an organ or tissue transplantation in order to reduce transplant rejection.

[0090] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0091] A "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically- acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0092] A "pharmaceutically-acceptable salt" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds.

[0093] The formulations comprising chemorepellent agents can optionally comprise medicinal agents, pharmaceutical agents, carriers, adjuvants, dispersing agents, diluents, and the like.

[0094] The chemorepellant agents can be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And

Practice of Pharmacy (9 ^th Ed. 1995). In the manufacture of a pharmaceutical formulation according to the invention, the chemorepellent agent (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier. The carrier can be a solid or a liquid, or both, and is preferably formulated with the fusion protein as a unit-dose formulation, for example, a tablet, which can contain from 0.01 or 0.5% to 95% or 99% by weight of the chemorepellent agent. One or more chemorepellent agents can be incorporated in the formulations of the invention, which can be prepared by any of the well-known techniques of pharmacy.

[0095] In some embodiments, an effective amount of a composition comprising a chemorepellent agent for administration to a' subject can be about 0.001 mg/kg/day- 1,000 mg/kg/day (e.g., about 0.005, 0.01, 0.015, 0.02, 0.025, 0.05, 0.075, 0.1, 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 mg/kg/day, and any range or value therein). [0096] The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

EXAMPLES

[0097] Example 1. Dog tissue transplantation into mice.

Iliotibial (IT)-bands from dog, either coated or without the CXCL12 (SDF-la) were transplanted (subcutaneous) into mice and the immune response was observed.

[0098] Materials:

1. Four C57BU6 mice

2. IT-bands from dog #4

3. CXCL12, lftg/ml, 200 pg per sample

4. Anesthetic solution

5. Dulbecco's Phosphate-Buffered Saline (DPBS) IX

6. Protease inhibitor

[0099] Procedure:

1. Pieces of IT-bands were cut and split in half, measured and rehydrated in DPBS IX +Protease inhibitor for 5 min at RT.

2. Half of the tissue samples were incubated with lftg/ml CXCL12 for 2 hours at RT (room Temp) on a rocker, and the other half of the tissues were incubated with DPBS IX for the same time and conditions.

3. Samples with CXCL12 were rinsed 3x with DPBS IX.

4. Anesthetized mice were shaved and tagged, small incision was made on the left side of the mouse back for the tissue without CXCL12and on the right side for the tissue coated with the CXCL12.

5. Tissues were placed into the mice and sutured. Next day after observation the mice looked normal and healthy and so, were returned to the animal facility.

6. Two mice remained for a week and two stayed for two weeks.

7. Tissues were removed after a week and two weeks for observation and staining.

8. Tissues from the one- week mice were fixed in 4% formaldehyde, embedded in paraffin and 3 sections were made. One section was stained with H&E and other two immunostained with antibodies.

9. Tissues from the two-week mice were cut in half. One half of the tissue was fixed with 4% formaldehyde and the other half was fixed by freezing with OCT (optimal cutting temperature)- media using liquid nitrogen. [0100] Results: Figs. 1A-1D and Figs. 2A-2D show the dog tissues within the skin layers in mice # 1779 and #1778 for the 1 week time point, and in mice # 1780 and 1782 for the 2 weeks post-transplantation time point. Figs. 3A-3F, 4A-4F and 5A-5F show the various views of the histology sections from the same dog tissues as in Figs. 1A-1D and Fig. 2A-2D. Haemotoxylin and eosin (H&E) staining was performed on these sections.

[0101] Discussion: One-week post transplantation, dog tissues on both sides of the mice were still present. Dog tissues on the left side, without having been coated with CXCL12, are embedded and covered with the skin layers compared to the right side tissues that were coated with CXCL12. After two weeks, the dog tissues on the left side are completely gone and on the right side they are still present without any damage. The histology staining confirmed the repellent function of the CXCL12 in this xenograft experiment.

[0102] The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.