POLARIZED TYPE-2 ALLOREACTIVE CD4(-CELLS FAIL TO INDUCE EXPERIMENTAL ACUTE CRAFT-VERSUS-HOST DISEASE() AND CD8(+) DONOR T)

Acute graft-vs-host disease (GVHD) is thought to be mediated by allore active T cells with a type 1 cytokine phenotype. To prevent the develo pment of acute GVHD, we have successfully polarized mature donor T cel ls toward a type 2 cytokine phenotype ex-vivo by incubating them with murine rIL-4 in a primary MLC. Polarized type 2 T cells were then tran splanted with T cell-depleted bone marrow cells into irradiated recipi ents across either MHC class II (bm12-->C57BL/6) or class I (bm1-->C57 BL/6) barriers, and the intensity of GVHD was measured by assessment o f several in vitro and in vivo parameters. The injection of polarized type 2 T cells abrogated the mitogen-induced production of IFN-gamma b y splenocytes from transplanted hosts on day 13 after bone marrow tran splantation (BMT). Injection of polarized type 2 T cells failed to ind uce secretion of the effector phase cytokine TNF-alpha by splenocytes stimulated with LPS both in vitro and in vivo, and survival of transpl anted mice after i.v. injection with LPS was significantly improved. F urthermore, cell-mixing experiments revealed that polarized type 2 T c ells were able to inhibit type 1 cytokine responses induced by naive T cells after BMT. These data demonstrate that both polarized CD4(+) an d CD8(+) type 2 alloreactive donor T cells can be generated in vitro f rom mature T cell populations. These cells function in vivo to inhibit type 1 T cell responses, and such inhibition attenuates the systemic morbidity of GVHD after BMT across both MHC class II or class I barrie rs in mice.