Mechanisms of unresponsiveness associated with pretransplant blood transfusion - cyclosporine-induced mixed lymphocyte chimerism

Abstract

Multiple pretransplant blood transfusions while under limited daily cyclosporine cover (PTBT-CsA) induce extensive rat renal allograft survival and antigen-specific non-responsiveness. The underlying mechanisms of this extensive allograft survival are not yet fully understood. We hypothesized that one of the potential contributing mechanisms to tolerance induction in PTBT-CsA-treated kidney recipients is the development of stable mixed chimerism, putatively due to the proliferation of stem cells capable of haematopoiesis in the transfused blood. BN rats served as whole blood and kidney donors. LEW rats served as recipients of the PTBT-CsA protocol and BN kidney transplants. Three weekly transfusions were given under concomitant limited CsA cover. Following these multiple primary sensitizations, antigen-specific splenic cellular responsiveness in vivo was normal in comparison with naive animals. However, these experimental splenocytes were non-specifically suppressed against third-party allodeterminants. At 100 days post-transplantation (T100) following tolerance induction to kidney allografts (secondary challenge), in vivo adoptive transfer experiments demonstrated the existence of potent splenic suppressor cells. In vitro suppressor cell assays confirmed that these cells were non-specific suppressor cells. However, following chimerism stabilization at T130, splenic antigen-specific suppressor cells became exclusively expressed in the tolerant animals, replacing the non-specific suppressor cells. At this time, splenic microchimerism was at peak levels and remained stable from T100 to T130. In conclusion, these findings demonstrate that sequential mechanisms of suppressor cell network expression are induced within a chimeric environment by blood-CsA immune modulation. Stable mixed lymphocyte chimerism and related immunomodulatory mechanisms may, therefore, play an important tolerogenic role in blood-CsA-induced non-responsiveness and in the beneficial effect of blood transfusion.