Cutting edge: Recipient MHC class II expression is required to achieve long-term survival of murine cardiac allografts after costimulatory blockade

To study the role of the direct and indirect pathways in achieving toleranc e, we used genetically altered mouse strains in two ways: 1) MHC class II-d eficient mice were used as donors of skin and cardiac grafts to eliminate t he direct CD4(+) T cell response, and 2) B6 II(-)4(+) mice, which are MHC c lass II-deficient mice expressing an MHC class II transgene only on thymic epithelium, were used as recipients of normal grafts. These mice cannot mou nt an indirect response. Eliminating the indirect pathway actually made it more difficult to achieve prolonged allograft survival when we used costimu latory blockade than when both pathways were available. Costimulatory block ade was ineffective even when CD4(+) T cells from normal animals were trans ferred into recipients that lacked MHC class II molecules. These results su ggest that an active CD4(+) response through the indirect pathway is necess ary for costimulatory blockade to be effective in prolonging allograft surv ival.