High incidence of donor-reactive delayed-type hypersensitivity reactivity in transplant patients.

Evidence of transplant recipient cellular sensitization towards donor antigens has rarely been directly measured. Rather, sensitization has been generally inferred by the presence of detectable allo-reactive or donor-reactive antibodies. In this study a newly developed delayed-type hypersensitivity assay was used to directly determine the incidence of post-transplant donor-reactive T-cell sensitization in a large cohort of kidney and simultaneous kidney-pancreas recipients. These results were compared with the presence of detectable circulating alloantibodies and with patient clinical outcome. We found an unexpectedly high incidence (52%) of donor-reactive delayed-type hypersensitivity reactivity in our study patients. Donor-reactive delayed-type hypersensitivity reactivity occurred at a much higher frequency than detectable alloantibodies (20%). Further, we found no correlation between the presence of alloantibodies and donor-reactive delayed-type hypersensitivity reactivity. We also found no correlation between the development of donor-reactive delayed-type hypersensitivity reactivity and the degree of donor and recipient HLA matching. Finally, the presence of detectable donor-reactive delayed-type hypersensitivity reactivity did not correlate with a worse clinical outcome at the time of these analyses. We conclude that in transplant recipients, the presence of circulating alloantibodies is a poor indicator of previous T-cell sensitization to donor antigens. We also conclude that our current immunosuppression strategies are relatively ineffective at blocking T-cell allosensitization, but are very effective at blocking the biological consequences of that allosensitization.

Clinical significance of MHC-reactive alloantibodies that develop after kidney or kidney-pancreas transplantation.

The purpose of this study was to determine the relationships between acute rejection, anti-major histocompatibility complex (MHC) class I and/or class II-reactive alloantibody production, and chronic rejection of renal allografts following kidney or simultaneous kidney-pancreas transplantation. Sera from 277 recipients were obtained pretransplant and between 1 month and 9.5 years post-transplant (mean 2.6years). The presence of anti-MHC class I and class II alloantibodies was determined by flow cytometry using beads coated with purified MHC molecules. Eighteen percent of recipients had MHC-reactive alloantibodies detected only after transplantation by this method. The majority of these patients produced alloantibodies directed at MHC class II only (68%). The incidence of anti-MHC class II, but not anti-MHC class I, alloantibodies detected post-transplant increased as the number of previous acute rejection episodes increased (p = 0.03). Multivariate analysis demonstrated that detection of MHC class II-reactive, but not MHC class I-reactive, alloantibodies post-transplant was a significant risk factor for chronic allograft rejection, independent of acute allograft rejection. We conclude that post-transplant detectable MHC class II-reactive alloantibodies and previous acute rejection episodes are independent risk factors for chronic allograft rejection. Implementing new therapeutic strategies to curtail post-transplant alloantibody production, and avoidance of acute rejection episodes, may improve long-term graft survival by reducing the incidence of chronic allograft rejection.