S Stepkowski

In vitro analysis of T cell-mediated cytotoxicity displayed by rat heart allograft recipients rendered unresponsive by total-lymphoid irradiation and extracted donor antigen

The addition of 3M KCl-extracted donor antigen (HAg) to immunosuppressive therapy with 16 Gy total lymphoid irradiation produces a significantly higher fraction of Wistar-Furth (WFu) recipients displaying indefinite survival of heterotopic buffalo (BUF) heart allografts, namely 80 versus 20%. The experiments presented herein analyzed the direct activity as well as estimated the potential precursor numbers at 1 and 3 months in treated recipients. At 1 month post-TLI/HAg therapy, recipients showed reduced proliferative responses in mixed lymphocyte reactions (MLR) in a specific pattern toward donor but not third-party stimulators. Both TLI/Graft and TLI/HAg/Graft groups showed a higher frequency of BUF antigen-directed T-cytotoxic cells (fTc) than TLI-treated, but nontransplanted, WFu hosts. In addition, the TLI/HAg group alone displayed alloantigen-specific suppressor cells that suppressed the MLR proliferative responses of normal spleen T cells against donor, but not third-party, alloantigens. At 3 months postirradition, both TLI/Graft and TLI/HAg/Graft groups displayed variable MLR proliferative responses toward donor and third-party alloantigens. Whereas nontransplanted, TLI-treated WFu rats recovered their fTc to normal levels at 3 months, the TLI and TLI/HAg treated recipients bearing functional heart allografts demonstrated significantly decreased splenic fTc. These results show that reduced numbers of cytotoxic cell precursors may afford more reliable indices of prolonged heart allograft survival than MLR responses. The observations suggest that TLI/HAg transplant hosts display both reduced cytotoxic precursors and activated suppressor elements.

LOCAL IMMUNOSUPPRESSION OF RAT CARDIAC, LIVER, AND SMALL BoWEL ALLOGRAFTS

Allotransplantation plays a critical role in the treatment of patients with end-stage renal, cardiac, hepatic and pulmonary diseases. Although systemic administration of immunosuppressive agents prevents graft rejection, toxic side effects cause the dysfunction of vital organs including kidney, liver and bone marrow.1–3 In addition, current immunosuppression is associated with an increased incidence of infection, diabetes, hypertension and malignancy in transplant recipients. To overcome these problems, different approaches are under consideration: (1) improvement of immunosuppressive protocols by development of new nontoxic drugs;4 (2) application of synergistic drug combinations to reduce individual drug doses, hence to decrease toxic side effects;5 (3) donor or graft pretreatment to reduce graft-versus-host immune response for small bowel transplantation6 and (4) local delivery of immunosuppressive agents to directly block intragraft events with reduction of systemic drug concentrations.7