Transplant tolerance and mixed chimerism

Transplant tolerance (also immunological tolerance or operational tolerance) is a state in which a transplant recipient durably accepts an allograft without ongoing immunosuppression and without rejection, while retaining the ability to respond to other antigens.[1][2] It is a long-standing goal of transplantation because it would eliminate the lifelong drug toxicity, infection, and malignancy risks that accompany chronic immunosuppression.[1][2] Mixed chimerism, the stable coexistence of donor- and recipient-derived hematopoietic (blood-forming) cells in one individual, is the most clinically advanced strategy investigated for deliberately inducing donor-specific tolerance.[2][3] Tolerance induction remains largely experimental and confined to specialized trials; it is not standard care.[1][2]

Concepts of tolerance

In transplantation, donor-specific tolerance means the recipient's immune system does not attack the graft's donor antigens but remains competent against pathogens and other foreign antigens, distinguishing it from generalized immunosuppression.[1][2] Operational tolerance is the clinical observation of stable graft function off all immunosuppression, regardless of the underlying mechanism; it is occasionally seen spontaneously, most often in some liver-transplant recipients and rarely in kidney recipients, and is the endpoint that tolerance-induction protocols seek to create reliably.[1][2]

The immunologic mechanisms that can produce tolerance are conventionally grouped as:[1][2]

• Central (thymic) deletion, elimination of developing donor-reactive T cells in the thymus, which is especially important when donor hematopoietic cells durably populate the recipient.
• Peripheral mechanisms, including clonal deletion or anergy of mature donor-reactive T cells, and active suppression by regulatory T cells (Tregs).

Studies in tolerant transplant recipients suggest an early role for regulatory T cells followed by gradual deletion of donor-reactive clones, with central deletion predominating in those with durable chimerism.[3]

Mixed chimerism

Chimerism describes the presence in one individual of cells from two genetically distinct sources.[2][3] Full (complete) chimerism, in which the recipient's hematopoietic system is entirely replaced by the donor's, is the routine outcome of conventional myeloablative allogeneic hematopoietic stem cell transplantation. Mixed chimerism, in which donor and recipient hematopoietic cells coexist, is the state intentionally created by tolerance-induction protocols for solid-organ transplantation.[2][3] The concept rests on classic experimental immunology: Owen's observation of natural blood-cell chimerism in cattle twins, and Billingham, Brent, and Medawar's demonstration of acquired immunological tolerance in mice, showed that exposure to foreign hematopoietic cells could render an animal tolerant of donor tissue.[1][2] Translating this to humans involves transplanting donor bone marrow or hematopoietic stem cells alongside (or before) the solid organ so that donor hematopoietic cells engraft and educate the recipient's immune system to accept donor antigens.[2][3]

Chimerism may be durable (persistent) or transient. In some human protocols, even transient chimerism that disappears within weeks has been followed by long-term tolerance, implying that mechanisms beyond ongoing chimerism, including a tolerogenic role of the kidney graft itself and peripheral regulation, sustain the tolerant state.[3][4]

Clinical experience

The most clinically advanced application has been in living-donor kidney transplantation, where combined kidney-and-hematopoietic-cell transplantation has been used to induce tolerance and permit withdrawal of immunosuppression in selected recipients.[3][4][5] Two landmark 2008 reports demonstrated proof of concept:[4][5]

• A Massachusetts General Hospital protocol used nonmyeloablative conditioning and combined HLA-mismatched kidney and bone marrow transplantation; recipients developed transient mixed chimerism, and several were maintained off all immunosuppression for years.[4]
• A Stanford University protocol combined kidney transplantation with hematopoietic-cell infusion (initially in HLA-matched pairs) to establish chimerism and withdraw immunosuppression.[5]

Subsequent follow-up across these and related programs has reported recipients maintained off immunosuppression for many years, with mixed and improving long-term results.[3] These protocols are technically demanding and carry risks, including the conditioning regimen's toxicity, engraftment syndrome, infection, and the small but serious possibility of graft-versus-host disease, and they have been pursued only in specialized centers and trials.[2][3] Outcomes vary by protocol and by HLA match, and some recipients have required resumption of immunosuppression for recurrent disease or rejection; tolerance induction is therefore not yet a routine clinical option.[3][4]

Significance and limitations

Reliable transplant tolerance would remove the principal long-term burden of transplantation, the complications of lifelong immunosuppression, and could improve graft longevity.[1][2] However, current chimerism-based approaches are limited by the morbidity of the conditioning required, inconsistent durability of tolerance, applicability mainly to living-donor settings, and the difficulty of extending them to deceased-donor and non-renal organs.[2][3] Research continues on less toxic conditioning, regulatory-cell (Treg) therapies, and reliable biomarkers to identify tolerant recipients in whom immunosuppression might be safely minimized or withdrawn; such withdrawal outside a trial is hazardous and not recommended.[1][2][3]

See also

• Transplant rejection
• Immunosuppression in transplantation
• Transplant immunology
• Graft-versus-host disease
• Human leukocyte antigen (HLA) and tissue typing
• Living donation

References

• Justiz Vargas AN, Sharma S, et al. Transplantation Immunology. StatPearls. NBK538218. https://www.ncbi.nlm.nih.gov/books/NBK538218/
• Kawai T, Sachs DH. Tolerance induction: hematopoietic chimerism. Curr Opin Organ Transplant. 2013;18(4):402-407. PMID:23838644. https://pubmed.ncbi.nlm.nih.gov/23838644/
• Oura T, Cosimi AB, Kawai T. Chimerism-based tolerance in organ transplantation: preclinical and clinical studies. Clin Exp Immunol. 2017;189(2):190-196. PMID:28369701. https://pmc.ncbi.nlm.nih.gov/articles/PMC5508349/
• Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008;358(4):353-361. PMID:18216355. https://pubmed.ncbi.nlm.nih.gov/18216355/
• Scandling JD, Busque S, Dejbakhsh-Jones S, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med. 2008;358(4):362-368. PMID:18216356. https://pubmed.ncbi.nlm.nih.gov/18216356/