Which type of hypersensitivity is responsible for organ/tissue transplant rejection?

Type IV Hypersensitivity Mediates Organ/Tissue Transplant Rejection

Type IV hypersensitivity (cell-mediated) is the primary mechanism responsible for organ/tissue transplant rejection. While antibody-mediated mechanisms (Type II) can also contribute to rejection, particularly in hyperacute and acute humoral rejection, the predominant immunological process underlying transplant rejection is cell-mediated immunity (Type IV) 1, 2.

Mechanisms of Transplant Rejection

• T-cell mediated rejection (Type IV hypersensitivity) involves direct recognition of donor HLA antigens by recipient T cells, leading to cellular infiltration and damage to the transplanted organ 1, 2.
• For cell-mediated rejection, T cells require multiple signals for activation, with the minimum being two signals: antigen recognition and costimulation 1.
• Activation of elements of the innate immune system, triggered by tissue injury during organ retrieval and ischemia-reperfusion, initiates and amplifies the adaptive T-cell response 2.
• Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection, particularly in the first two months after transplantation 3.

Types of Transplant Rejection

Hyperacute Rejection

• Occurs within minutes to hours after transplantation 4.
• Primarily mediated by preformed donor-specific antibodies (Type II hypersensitivity) 4.
• Results in rapid graft failure due to complement activation and vascular thrombosis 4.

Acute Rejection

• Occurs days to months after transplantation 5.
• Can be T-cell mediated (Type IV) or antibody-mediated (Type II) 5.
• T-cell mediated rejection involves infiltration of T cells into the graft, leading to tissue damage 5, 2.
• Antibody-mediated rejection involves donor-specific antibodies binding to endothelial cells, activating complement, and causing vascular damage 5.

Chronic Rejection

• Develops months to years after transplantation 6.
• Involves both cellular (Type IV) and humoral (Type II) mechanisms 6.
• Results in progressive fibrosis and loss of graft function 6.

Evidence Supporting Type IV Hypersensitivity in Transplant Rejection

• The pathogenesis of transplant rejection involves T-cell recognition of donor HLA antigens, leading to activation of cytotoxic T cells that directly damage the allograft tissue 2.
• Immunosuppressive medications targeting T-cell function (such as azathioprine) are effective in preventing rejection, supporting the critical role of cell-mediated immunity 7.
• Azathioprine suppresses cell-mediated immunity and is used to inhibit renal homograft rejection by suppressing T-cell effects 7.
• The vascular endothelium is the primary point of contact for both cellular and antibody-mediated rejection, with enlarged or swollen endothelial cells reflecting activation in response to immune attack 5.

Crossmatch Testing and HLA Matching

• Flow cytometry or complement-dependent cytotoxicity assays are used to detect preformed antibodies against donor tissues, which can predict hyperacute rejection 5.
• A positive crossmatch using sera with IgG antibodies to HLA antigens is a contraindication to transplantation 5.
• Optimal matching of donor and recipient HLA antigens can reduce the incidence of acute rejection episodes and improve long-term graft survival 5.
• The American Society of Transplantation recommends performing high-resolution DNA typing for all HLA loci to fully characterize potential allele-level mismatches 8.

Management Strategies for Transplant Rejection

• Immunosuppressive medications targeting T-cell function are the cornerstone of preventing and treating transplant rejection 5, 7.
• Various immunosuppressive agents are used based on the type of rejection, including:
  • Mycophenolate and anti-thymocyte globulin for maintenance immunosuppression 5.
  • Rituximab for antibody-mediated rejection 5.
  • Plasma exchange for removing donor-specific antibodies in antibody-mediated rejection 5, 9.
• Therapeutic plasma exchange is recommended for selected patients with antibody-mediated rejection but has not been shown to improve overall survival 9.

Conclusion

While multiple immune mechanisms contribute to transplant rejection, Type IV hypersensitivity (cell-mediated immunity) is the predominant mechanism responsible for organ/tissue transplant rejection. T cells recognize donor antigens, become activated, and directly damage the transplanted tissue. Antibody-mediated mechanisms (Type II hypersensitivity) also play important roles, particularly in hyperacute rejection and some forms of acute rejection, but the fundamental immunological process underlying most forms of transplant rejection is cell-mediated immunity 1, 2, 6.