Transplant immunology

Transplant immunology is the study of the immune response to a transplanted graft and of the means used to prevent and treat rejection.[1] When an organ or tissue is transplanted between genetically non-identical members of the same species (an allograft), the recipient's immune system recognizes foreign human leukocyte antigens (HLA) and other antigens on the graft and can mount a destructive response.[1] Clinical transplantation therefore depends on matching and compatibility testing before transplantation and on immunosuppression afterward. Central concepts include the HLA system and tissue typing, ABO compatibility, antibody screening (panel-reactive antibody and the crossmatch), the categories of rejection, and the drug classes used to prevent it.[1][2]

The HLA system and tissue typing

The HLA system is the human major histocompatibility complex (MHC), a highly polymorphic set of cell-surface molecules that present antigens to T cells.[1] Class I molecules (HLA-A, -B, -C) are expressed on most nucleated cells; class II molecules (HLA-DR, -DQ, -DP) are expressed mainly on antigen-presenting cells.[1] Because HLA is so polymorphic, unrelated individuals rarely match fully. Tissue typing determines a candidate's and donor's HLA alleles using molecular methods (PCR-based typing and next-generation sequencing). The degree of HLA matching influences rejection risk and, for some organs (notably kidney), allocation and long-term outcomes.[1]

ABO compatibility

ABO blood-group antigens are expressed on vascular endothelium, so ABO compatibility is generally required for solid-organ transplantation; transplanting across an incompatible ABO barrier risks hyperacute, antibody-mediated graft loss from preformed anti-A/anti-B isoagglutinins.[3] ABO-incompatible transplantation is nonetheless performed in selected settings (for example, some living-donor kidney and pediatric heart transplants) using desensitization to remove antibody and the phenomenon of accommodation, in which the graft becomes resistant to antibody-mediated injury.[3]

Sensitization, PRA, and cPRA

Exposure to foreign HLA, through prior transplantation, pregnancy, or transfusion, can lead a candidate to form anti-HLA antibodies, a state called sensitization.[1][4] The breadth of sensitization is expressed as the panel-reactive antibody (PRA) and, in current U.S. allocation, the calculated PRA (cPRA), the percentage of donors against whom the candidate has antibodies.[4] Highly sensitized candidates (high cPRA) are harder to match and receive allocation priority. Antibodies directed specifically against a given donor's HLA are donor-specific antibodies (DSA), which may be preformed or develop after transplantation (de novo) and are a principal cause of antibody-mediated rejection.[1][5]

The crossmatch

The crossmatch tests a candidate's serum against a specific donor's cells to detect DSA before transplantation.[6] Methods include the historical complement-dependent cytotoxicity (CDC) crossmatch, the more sensitive flow-cytometry crossmatch, and the virtual crossmatch, which predicts compatibility by comparing the candidate's identified antibody specificities (from single-antigen bead assays) against the donor's HLA typing without physically mixing cells.[6] A positive crossmatch against relevant DSA generally contraindicates transplantation because of the risk of hyperacute or early antibody-mediated rejection.[6]

Rejection

Rejection is categorized by timing and mechanism, and biopsy findings are graded using the Banff classification:[2]

• Hyperacute rejection, minutes to hours after reperfusion, caused by preformed DSA or ABO incompatibility; now rare because of crossmatching and ABO compatibility.
• Acute rejection, days to months; T-cell-mediated (cellular) rejection and/or antibody-mediated rejection (AMR) (the latter associated with DSA and, in tissue, with C4d deposition). Acute rejection is often treatable.
• Chronic rejection, months to years; progressive, largely irreversible graft injury and fibrosis (manifesting in organ-specific forms such as cardiac allograft vasculopathy or chronic lung allograft dysfunction).[2]

Immunosuppression

Immunosuppression is given in two phases:[7]

• Induction, intense immunosuppression at the time of transplantation, using a lymphocyte-depleting agent (such as anti-thymocyte globulin) or an interleukin-2 receptor antagonist (basiliximab).
• Maintenance, lifelong therapy, typically combining drug classes: calcineurin inhibitors (tacrolimus, ciclosporin), antiproliferative agents (mycophenolate, azathioprine), mTOR inhibitors (sirolimus, everolimus), and corticosteroids.[7]

Treatment of established rejection depends on type (for example, corticosteroid pulses or lymphocyte depletion for cellular rejection; plasmapheresis, intravenous immunoglobulin, and other agents for AMR).[2][7] Chronic immunosuppression carries substantial risks, including opportunistic infection (cytomegalovirus, BK virus, Pneumocystis), malignancy (including post-transplant lymphoproliferative disorder), nephrotoxicity, and metabolic effects such as new-onset diabetes after transplantation.[7]

Graft-versus-host disease

In graft-versus-host disease (GVHD), immune cells transferred with the graft attack the recipient's tissues, the reverse of rejection.[8] GVHD is chiefly a complication of hematopoietic stem-cell (bone marrow) transplantation but can rarely occur after solid-organ or tissue transplantation. Diagnosis is supported by the Billingham criteria, and it most often affects the skin, gut, and liver.[8]

Tolerance

Transplant tolerance is the goal of durable graft acceptance without ongoing immunosuppression.[9] Experimental and selected clinical strategies, notably the induction of mixed chimerism, in which donor and recipient hematopoietic cells coexist, have achieved tolerance in some recipients, but reliable, broadly applicable tolerance remains a research objective rather than standard practice.[9]

See also

• Organ transplantation · Kidney transplantation
• Deceased donation · The donation pathway

References

• Justiz Vargas AN, et al. Transplantation Immunology (HLA, MHC, sensitization). StatPearls. NBK538218. https://www.ncbi.nlm.nih.gov/books/NBK538218/
• Transplant Rejection (hyperacute/acute/chronic; Banff). StatPearls. NBK553074. https://www.ncbi.nlm.nih.gov/books/NBK553074/
• ABO compatibility and ABO-incompatible transplantation. PMC5338156. https://pmc.ncbi.nlm.nih.gov/articles/PMC5338156/
• Calculated panel-reactive antibody (cPRA) and sensitization. OPTN/American Journal of Transplantation. https://www.amjtransplant.org/article/S1600-6135(22)19538-9/fulltext
• Donor-specific antibodies (DSA): preformed vs de novo. Front Med. 2022. https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.943502/full
• Crossmatch (CDC, flow, virtual). PMC10727546. https://pmc.ncbi.nlm.nih.gov/articles/PMC10727546/
• Immunosuppression in transplantation (induction/maintenance; complications). StatPearls. NBK558995. https://www.ncbi.nlm.nih.gov/books/NBK558995/
• Graft-versus-host disease (Billingham criteria). StatPearls. NBK538235. https://www.ncbi.nlm.nih.gov/books/NBK538235/
• Transplant tolerance and mixed chimerism. PMC6059978. https://pmc.ncbi.nlm.nih.gov/articles/PMC6059978/