Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: Considerations for the allogeneic transplantation therapy of leukemia and lymphoma

Allogeneic stem cell transplantation (SCT) represents a curative treatment option for patients with leukemia and lymphoma. T lymphocytes contained in the allograft mediate a graft-versus-leukemia (GVL) effect and prevent graf t rejection; however, T cells also initiate graft-versus-host disease (GVHD ). Identification of T cell populations which mediate a GVL effect and prev ent rejection with reduced GVHD will likely improve transplantation outcome . T cells exist in four functionally-defined populations, the CD4(+), Th1/T h2 and CD8(+), Tc1/Tc2 subsets. Th1-type CD4 cells primarily secrete type I cytokines (IL-2 and IFN-gamma), whereas Th2 cells secrete type II cytokine s (IL-4, IL-5, and IL-10). Similarly, the CD8+ Tc1 and Tc2 cells differenti ally secrete the type I and type II cytokines, respectively. In addition to cytokine secretion, Tc1 and Tc2 populations mediate cytolytic effects, wit h Tc1 cells utilizing both perforin- and fas-based killing pathways, wherea s Tc2 cells primarily utilize perforin-mediated cytolysis. In murine transplantation models of graft rejection, GVHD, and GVL effects, we have evaluated such functional T cell subsets for their ability to diff erentially mediate and regulate transplantation responses. These studies de monstrate that donor Th2 cells do not initiate acute GVHD, and can regulate the GVHD mediated by unmanipulated donor T cells without impairing alloeng raftment. Additional experiments have shown that allospecific donor Tc2 cel ls result in reduced GVHD, and mediate a significant GVL effect. Thirdly, w e have demonstrated that non-host reactive Tc2 cells with veto-like activit y can potently abrogate marrow rejection independent of GVHD. Together, the se results demonstrate that functionally-defined donor Th2 and Tc2 populati ons play an important role in the regulation of GVHD, the prevention of gra ft rejection, and the mediation of GVL effects, and suggest that utilizatio n of Th2 and Tc2 cells in clinical allogeneic SCT may have potential for im proving treatment outcome.