Graft versus host disease (GVHD) is the major limitation to the widespread utilization of allogeneic stem cell transplantation in the treatment of patients with hematological malignancies, solid tumors, bone marrow failure syndromes and congenital diseases. GVHD is mediated by alloreactive donor T cells that recognize major or minor histocompatibility antigens presented by recipient antigen presenting cells. This process leads to a cascade of events that generate proinflammatory cytokines and causes the destruction of recipient cells. The expansion of alloreactive T cells is controlled both by homeostatic proliferation and regulatory T cells. CD4+/CD25+ Treg cells have been shown to be capable of inhibiting GVHD in multiple different murine models and the expansion of these cells for clinical use is feasible. However, little is known about the mechanism of activity of Treg cells in the prevention of GVHD. Whether Treg cells function to suppress alloreactive T cell proliferation in secondary lymphoid tissue or GVHD target organs is not known. The proteins responsible for the migration of Treg cells into secondary lymphoid tissue have not been demonstrated and the affect of blocking the function of the migration of Treg cells is not clear Our group has recently found that the administration of Treg cells that express L-selectin potently inhibited GVHD while Lselectinlo Treg cells had little effect. Additionally, we have recently shown that Treg cells express a different pattern of chemokine receptors after activation, that the chemokine receptor, CCR5, is markedly increased after activation, and that the absence of CCR5 on donor T cells markedly increased the severity of GVHD in irradiated recipient animals. In this proposal, we will investigate the migration of Treg cells in GVHD models. The following three specific aims will be evaluated:
Aim 1) : To evaluate the function of L-selectin, CCR5 and CCR7 in the migration of Treg cells into secondary lymphoid organs.
Aim 2) : To evaluate if Treg cells migrate to parenchymal organs in which GVHD occurs in vivo and if this migration is dependent on the expression of chemokine receptors such as CCR4, CCR5 or CCR8.
Aim 3) : (a) To determine if Treg cell function in GVHD models is dependent on migration to SLT. (b) To determine if the migration of Treg cells is dependent on the presence of Peyer's patches (PP) or the spleen. The overall goals of this work are to provide a better understanding of the mechanism of activity of Treg cells prior to a clinical trial evaluating their effects in blocking GVHD.
