- Dr Anna Valujskikh, Principal Investigator
- Cleveland Clinic, Cleveland, USA
- Alloantibody Production in Sensitized Transplant Recipients
Immune response against donor antigens is a serious problem undermining the function and survival of organs transplanted to treat end-stage organ disease. While T cells play a central role in initiating donor-specific immune responses after transplantation, donor-reactive alloantibodies mediate a substantial proportion of rejection episodes and contribute to chronic allograft rejection. Despite advances in immunosuppression and routine panel reactive antibody screening prior to transplantation, 15-25% of transplant recipients develop de novo alloantibody within one year post transplant. Production of high levels of pathogenic alloantibodies requires interactions between antibody-secreting B cells and helper CD4+ T cells reacting to the same set of donor antigens. Currently used therapies efficiently control functions of naïve helper T cells. However, the T cell repertoire of many human transplant recipients contains antigen-experienced memory T cells reactive to donor alloantigens. These memory cells arise due to previous sensitization to alloantigens through blood transfusions, pregnancies or previous transplants or as a result of environmental exposure and chance cross-reactivity to donor alloantigens. Due to their enhanced survival, activation and trafficking properties, memory T cells precipitate allograft rejection despite immunosuppression or conventional costimulatory blockade. Our published data and preliminary results suggest that donor-specific memory CD4+ T cells can be major contributors to the induction of de novo alloantibodies in T cell-sensitized recipients. Despite high clinical relevance, the mechanisms of help provided by alloreactive memory CD4+ T cells for alloantibody production are poorly understood and will be the focus of this study. The proposed experiments will identify molecular targets for future therapies aimed at preventing de novo alloantibody development in T cell-sensitized transplant patients.