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CN-121985901-A - Methods for monitoring potential rejection indicators in allograft recipients

CN121985901ACN 121985901 ACN121985901 ACN 121985901ACN-121985901-A

Abstract

The present invention relates to methods of monitoring potential indications of allogeneic organ rejection by monitoring transplanted hair follicles from the same donor as the transplanted organ, and performing immunosuppressive therapy or modifying immunosuppressive therapy to ameliorate or prevent the occurrence of acute or chronic organ rejection. The methods of the invention can also be used to select candidate allograft solid organ donors for recipients, as well as to improve the incidence of acute rejection of transplanted allograft solid organs (e.g., kidneys).

Inventors

  • F. Popescu

Assignees

  • 头发重建外科医院有限责任公司

Dates

Publication Date
20260505
Application Date
20240530
Priority Date
20230530

Claims (16)

  1. 1. A method for monitoring a potential indication of organ rejection in a recipient previously transplanted with an allogeneic solid organ, the method comprising: (A) Transplanting one or more allogeneic follicular units from the same donor of the solid organ to one or more sites on the recipient's skin; (B) Monitoring one or more potential acute or chronic transplant rejection indicators of the recipient by monitoring the one or more follicular unit placement sites for an indication of inflammation and an immune response to one or more transplanted follicular units, wherein detection of an indication of inflammation and an immune response to one or more transplanted follicular units indicates an immune response and a potential rejection of a transplanted solid organ, and (C) If one or more indicators of inflammation and immune response to one or more transplanted follicular units are detected: (i) Subjecting the subject to or modifying the subject's existing immunosuppressive therapy to ameliorate or prevent the occurrence of acute or chronic organ rejection, and/or (Ii) Additional diagnostic procedures were performed to confirm the occurrence of acute or chronic organ rejection.
  2. 2. The method for monitoring potential indications of organ rejection of a recipient previously transplanted with an allogeneic solid organ according to claim 1, wherein the follicular unit is placed at one or more sites on the scalp, forearm, upper arm, lower leg, lower thigh, upper thigh, abdomen, upper back, or lower back area.
  3. 3. The method for monitoring the potential indication of organ rejection in a recipient who has previously transplanted an allogeneic solid organ according to claim 1 or 2, wherein the one or more potential acute or chronic transplant rejection indications are detection of one or more of an antibody-mediated response, an undesired allogeneic response, an acute or chronic host versus graft disease, reformation of donor-specific Human Leukocyte Antigen (HLA) antibodies, an increase in multicellular T cell concentration, an increase in perifollicular funnel-isthmus lymphocyte infiltration, and an imbalance in the CD4 to CD 8T cell ratio at the one or more follicular unit placement sites.
  4. 4. A method for monitoring potential indications of organ rejection in a recipient who has previously been transplanted with an allogeneic solid organ according to any one of claims 1-3, wherein the recipient is subjected to immunosuppressive therapy or is modified by pre-existing immunosuppressive therapy, wherein the therapy comprises administration of one or more of corticosteroids, cytostatic drugs, anti-tnfa antibodies, IL-2 receptor inhibitors, or other antibody-based immunosuppressive therapies.
  5. 5. The method of claim 4, wherein the corticosteroid is prednisone, the cytostatic drug is tacrolimus, mycophenolic acid, mycophenolate mofetil, or cyclosporine, and the IL-2 receptor inhibitor is basiliximab.
  6. 6. The method for monitoring potential indications of organ rejection in a recipient previously transplanted with an allogeneic solid organ according to any one of claims 1-5, wherein the donated organ is a kidney or viable portion thereof.
  7. 7. A method of selecting a candidate allogeneic solid organ donor for a recipient, the method comprising: (A) Transplanting one or more follicular units excised from one or more candidate organ donors, and placing the excised follicular units at one or more sites on the recipient's skin; (B) Monitoring the one or more follicular unit placement sites for an indication of inflammation and immune response to one or more transplanted follicular units, wherein detection of an indication of inflammation and immune response to one or more transplanted follicular units indicates potential rejection of a transplanted solid organ from the donor; (C) If no indication of inflammation and immune response to one or more transplanted follicular units is detected, or a therapeutically acceptable indication is detected, selecting one or more donor candidates for organ harvesting, and (D) The donated organ is transplanted to the recipient.
  8. 8. The method of selecting a candidate allogeneic solid organ donor for a recipient according to claim 7, wherein the follicular unit is placed at one or more sites on the scalp, forearm, upper arm, lower leg, lower thigh, upper thigh, abdomen, upper back, or lower back area.
  9. 9. The method of selecting a candidate allogeneic solid organ donor for a recipient according to claim 7 or 8, wherein the one or more potential acute or chronic transplant rejection indications are detection of one or more of an antibody-mediated response, an undesired allogeneic response, an acute or chronic host versus graft disease, reformation of donor-specific Human Leukocyte Antigen (HLA) antibodies, an increase in multicellular T cell concentration, an increase in perifollicular funnel-isthmus lymphocyte infiltration, and an imbalance in the CD4 to CD 8T cell ratio at the one or more follicular unit placement sites.
  10. 10. The method of selecting a candidate allogeneic solid organ donor for a recipient according to any one of claims 7-9, wherein the donated solid organ is a kidney.
  11. 11. A method for improving the incidence of acute rejection of transplanted allograft solid organs in a recipient, the method comprising: (A) Transplanting one or more allogeneic follicular units from a donor into which an allogeneic solid organ is transplanted to one or more sites on the skin of the recipient; (B) Monitoring the recipient for one or more potential indications of acute transplant rejection by monitoring the one or more follicular unit placement sites for an indication of inflammation and an immune response to one or more transplanted follicular units, wherein detection of an indication of inflammation and an immune response to one or more transplanted follicular units indicates acute rejection of a transplanted solid organ, and (C) If one or more indications of acute rejection are detected, the subject is subjected to an immunosuppressive therapy or an existing immunosuppressive therapy of the subject is modified to ameliorate the acute rejection of the transplanted organ.
  12. 12. The method for improving the incidence of acute rejection of transplanted allograft solid organs of claim 11 wherein the follicular unit is placed at one or more sites on the scalp, forearm, upper arm, lower leg, lower thigh, upper thigh, abdomen, upper back or lower back area.
  13. 13. The method for ameliorating the occurrence of acute rejection of transplanted allograft solid organs according to claim 11 or 12, wherein one or more potential acute or chronic transplant rejection indications are detection of one or more of an antibody mediated response, an undesired allogeneic response, an acute or chronic host versus graft disease, reformation of donor-specific Human Leukocyte Antigen (HLA) antibodies, an increase in multicytotoxic T cell concentration, an increase in perifollicular funnel-isthmic lymphocyte infiltration, and a CD4 to CD 8T cell ratio imbalance at the one or more follicular unit placement sites.
  14. 14. The method for improving the incidence of acute rejection of transplanted allograft solid organs of any one of claims 11-13 wherein the recipient is subjected to an immunosuppressive treatment or a modified pre-existing immunosuppressive treatment, wherein the treatment comprises administration of one or more of a corticosteroid, a cytostatic drug, an anti-tnfa antibody, an IL-2 receptor inhibitor, or other antibody-based immunosuppressive treatment.
  15. 15. The method of claim 14, wherein the corticosteroid is prednisone, the cytostatic drug is tacrolimus, mycophenolic acid, mycophenolate mofetil, or cyclosporine, and the IL-2 receptor inhibitor is basiliximab.
  16. 16. The method for improving the incidence of acute rejection of transplanted allograft solid organs of any one of claims 11-15 wherein the donated organ is a kidney.

Description

Methods for monitoring potential rejection indicators in allograft recipients Cross Reference to Related Applications The present application claims priority from U.S. provisional application No. 63/504,885 filed 5/30/2023, the disclosure of which is incorporated herein by reference. Background The need for long-term immunosuppressive therapy has been a major obstacle in considering allogeneic hair transplantation between two histocompatible individuals. Previous cases of both allografts have only been reported to involve Bone Marrow (BM) transplant recipients, and thus, in addition to HLA compatibility, the inherent chimeric immune tolerance of this procedure eliminates the need for immunosuppressive therapy 3,4. In the absence of chimeric immune tolerance, human-to-human hair transplantation between two individuals that are not related but histocompatible is a viable option for selected patients who already require lifelong immunosuppressive therapy. Since solid organ transplants are performed annually more than bone marrow transplants, solid organ transplant recipients constitute a larger population of transplant recipients that may benefit from human-to-human hair transplants based on proven histocompatibility, successful solid organ transplants, and pre-existing conditions for life-long immunosuppressive therapy. In addition, the procedure used to harvest the donor hair follicle (follicular unit excision (follicular unit excision, FUE) technique) is less invasive, making the donor harvesting procedure more acceptable to matched donors. Disclosure of Invention Applicants have recognized that transplanted allogeneic hair follicles can act as a proxy for the feasibility of allogeneic transplantation of solid organs (e.g., kidneys). According to one aspect of the invention, a method of monitoring a subject previously transplanted with an allogeneic solid organ for an indication of organ rejection has the steps of (A) transplanting one or more allogeneic follicular units from the same donor of the solid organ to one or more sites on the skin of the subject, (B) monitoring the subject for one or more indications of inflammation and immune response by monitoring one or more follicular unit placement sites for one or more transplanted follicular units, wherein detection of an indication of inflammation and immune response for one or more transplanted follicular units indicates an immune response and a potential rejection of the transplanted solid organ, and (C) if an indication of inflammation and immune response for one or more transplanted follicular units is detected, (i) conducting immunosuppressive therapy or modifying the subject's existing immunosuppressive therapy to ameliorate or prevent the occurrence of acute or chronic organ rejection, and/or (ii) conducting additional diagnosis to confirm or chronic organ rejection procedures. Follicular units may be placed at one or more locations on the scalp, forearm, upper arm, lower leg, lower thigh, upper thigh, abdomen, upper back, or lower back area. One or more potential acute or chronic transplant rejection indications are detection of one or more of an antibody-mediated response, an undesired allogeneic response, acute or chronic host versus graft disease (acute or chronic host versus GRAFT DISEASE), reformation of donor-specific Human Leukocyte Antigen (HLA) antibodies, an increase in multi-cytotoxic T cell concentration, an increase in perifollicular funnel-isthmus lymphocyte infiltration (AN INCREASE IN perifollicular infundibulo-isthmal lymphocytic infiltrates), and an imbalance in CD4: CD 8T cell ratio at one or more follicular unit placement sites. Subjecting or modifying a pre-existing immunosuppressive treatment to a subject, wherein the treatment comprises administering one or more of a corticosteroid, a cytostatic drug, an anti-tnfα antibody, an IL-2 receptor inhibitor, or other antibody-based immunosuppressive treatment. The corticosteroid may be, for example, prednisone, the cytostatic drug may be, for example, tacrolimus, mycophenolic acid (mycophenolate), mycophenolate mofetil (mycophenolate mofetil) or cyclosporine, and the IL-2 receptor inhibitor may be basiliximab. In another aspect of the invention, a method of selecting a candidate allogeneic solid organ donor for a recipient includes the steps of (A) transplanting one or more follicular units excised from one or more candidate organ donors and placing the excised follicular units at one or more locations on the recipient's skin, (B) monitoring the one or more follicular unit placement locations for an indication of inflammation and immune response to one or more transplanted follicular units, wherein detection of an indication of inflammation and immune response to one or more transplanted follicular units indicates potential rejection of the transplanted solid organ from the donor, (C) selecting one or more donor candidates for organ harvesting if no indication of inflammation and i