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Purpose of Review: Significant advancements have been made in the field of vascularized composite allotransplantation (VCA); however, like solid organ transplantation, bypassing the recipient's immune response remains a significant obstacle to long-term allograft survival. Therefore, strategies to overcome acute and chronic rejection and minimize immunosuppressive therapy are crucial for the future of VCA. This review highlights recent attempts to induce tolerance in VCA and discusses key findings through a clinical lens., Recent Findings: Promising VCA tolerance protocols are being investigated, with five recent studies illustrating various successes. These preclinical approaches demonstrate a correlation between the presence of donor-derived T cells and VCA tolerance, the importance of using clinically available reagents within preclinical protocols, and the ability to induce sustained tolerance through nonmyeloablative methods. Furthermore, environmental factors, such as NB-UVB light are being investigated for their immunomodulation properties and may influence VCA graft rejection., Summary: To widen the scope of VCA, minimization of immunosuppression is needed. Overall, tolerance induction protocols should have a low-toxicity level, minimally invasive induction therapies, and utilize short-term immunosuppressive medications. By examining the milestones of recent studies, researchers can gain new technical approaches to immune modulation and make data-driven amendments to tolerance protocols in preparation for clinical translation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We have previously demonstrated that tolerance to a vascularized composite allograft (VCA) can be achieved after the establishment of mixed chimerism. We test the hypothesis that tolerance to a VCA in our dog leukocyte antigen-matched canine model is not dependent on the previous establishment of mixed chimerism and can be induced coincident with hematopoietic cell transplantation (HCT)., Methods: Eight dog leukocyte antigen-matched, minor antigen mismatched dogs received 200 cGy of radiation and a VCA transplant. Four dogs received donor bone marrow at the time of VCA transplantation (group 1), whereas a second group of four dogs did not (group 2). All recipients received a limited course of postgrafting immunosuppression. All dogs that received HCT and VCA were given donor, third-party, and autologous skin grafts., Results: All group 1 recipients were tolerant to their VCA (>62 weeks). Three of the four dogs in group 2 rejected their VCA transplants after the cessation of immunosuppression. Biopsies obtained from the muscle and skin of VCA from group 1 showed few infiltrating cells compared with extensive infiltrates in biopsies of VCA from group 2. Compared with autologous skin and muscle, elevated levels of CD3+ FoxP3+ T-regulatory cells were found in the skin and muscle obtained from the VCA of HCT recipients. All group 1 animals were tolerant to their donor skin graft and promptly rejected the third-party skin grafts., Conclusion: These data demonstrated that donor-specific tolerance to all components of the VCA can be established through simultaneous nonmyeloablative allogeneic HCT and VCA transplantation protocol.

Background: Allogeneic hematopoietic cell transplantation provides a reliable method for inducing tolerance toward solid organ grafts. However, this procedure can result in graft-versus-host disease, thereby limiting its application. Here, we test the hypothesis that mixed chimerism can be intentionally reverted to host hematopoiesis without rejection of a kidney graft., Methods: Recipient dogs were given 2-Gy total-body irradiation (TBI) before and a short course of immunosuppression after marrow infusion from dog leukocyte antigen-identical littermates. All dogs achieved stable mixed chimerism. After a mean of 20 weeks, one cohort of dogs received kidney transplants from their respective marrow donors. Subsequently, recipients were reconditioned with 2-Gy TBI and given autologous granulocyte colony-stimulating factor-mobilized leukocytes (recipient leukocyte infusion [RLI]) that had been collected before marrow transplantation., Results: Dogs receiving a second TBI and RLI without a kidney transplant rejected their donor hematopoietic graft within 3 weeks. Dogs that received kidney grafts, followed by a second TBI and RLI, rejected their marrow graft without rejecting their transplanted kidneys for periods greater than 1 year., Conclusion: Mixed chimerism may be clinically reverted to 100% recipient without rejection of a kidney allograft. This finding may have application toward minimizing the risk of graft-versus-host disease in solid organ transplantation patients given hematopoietic cell transplantation from human leukocyte antigen-identical donors.

Composite tissue allograft (CTA) transplantation, such as the clinical face and hand transplants, has now been performed in multiple centers across the world. The transplants have successfully treated complex injuries that have either failed conventional approaches or where autologous reconstruction could not restore both form and function. CTA transplantation has the potential to improve outcomes over traditional techniques. However, the widespread application of CTA transplantation continues to be limited by the need for chronic immunosuppression. Due to the small numbers of CTA transplants performed, any modification in the immunosuppression used will likely be based from the solid organ literature. The renal transplantation literature has served as the basis for the current selection of CTA drug regimens and in this article we review the evidence in the renal transplant literature for the selection of immunosuppressive regimens. The study then compares the regimens used in both the face and hand transplantation with those regimens currently used for renal transplantation., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The emerging field of composite tissue transplantation offers the potential to replace lost tissues from cadaveric sources. Two major obstacles currently limit the future of composite tissue allotransplantation. The first is chronic rejection, attributed to both antibody deposition and cell-mediated destruction of transplanted tissue. The second obstacle is complications associated with the chronic use of immunosuppressive agents. Our laboratory has been investigating several strategies to induce tolerance to limb tissue allografts to provide solutions to many of the current limitations in allotransplantation. Three strategies show promise in the ability to induce tolerance to organ allografts. The first involves genetic matching at the HLA loci followed by a short course of immunosuppression. The second is the application of a "mixed chimerism" regimen followed by transplantation. The third is costimulatory blockade using a short course of monoclonal antibodies, such as anti-CD40 ligand and CTLA4-Ig after transplantation. Inducing a state of tolerance to limb allografts would eliminate the need for chronic immunosuppression and may also prevent the onset of chronic rejection. The ability to induce allograft tolerance would greatly expand the indications for composite tissue transplantation.