Secondary lymphoid organs contribute to, but are not required for the induction of graft-versus-host responses following allogeneic bone marrow transplantation: a shifting paradigm for T cell allo-activation.

Graft-versus-host disease (GVHD) remains the major complication of allogeneic bone marrow transplantation (allo-BMT). GVHD fundamentally depends upon the activation of donor T cells by host antigen-presenting cells (APCs), but the precise location of these interactions remains uncertain. We examined the role of secondary lymphoid organs (SLO) in the induction of GVHD by using homozygous aly/aly mice that are deficient in lymph nodes (LNs) and Peyer's patches (PPs). Lethally irradiated, splenectomized, aly/aly (LN/PP/Sp-/-) mice and sham-splenectomized, aly/+ (LN/PP/Sp+/+) mice received BMT from either syngeneic (aly/aly) or allogeneic, major histocompatibility complex (MHC) disparate donors. Surprisingly, although LN/PP/Sp-/- allo-BMT recipients experience a survival advantage, they developed significant systemic and target organ GVHD that is comparable to LN/PP/Sp+/+ controls. Early after allo-BMT, the activation and proliferation of donor T cells was significantly greater in the BM cavity of LN/PP/Sp-/- mice compared to LN/PP/Sp+/+ controls. Donor T cells in LN/PP/Sp-/- mice demonstrated cytolytic activity in vitro, but Graft vs Leukemia (GVL) activity could be overcome by increasing the tumor burden. These data suggest that SLO contribute to, but are not required for, allogeneic T cell responses, and suggest that the BM may represent an alternative, albeit less efficient site for T cell activation following allo-BMT.

CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation.

Acute graft-versus-host disease (GVHD) and leukemic relapse are serious complications of allogeneic stem-cell transplantation (SCT). Recruitment of activated T cells to host target tissues or sites of leukemic infiltration (graft-versus-leukemia [GVL]) is likely mediated by chemokine receptor-ligand interactions. We examined the contribution of donor cell CCR1 expression to the development of GVHD and GVL using a well-established murine SCT model (B6 --> B6D2F1) and CCR1-deficient mice (CCR1(-/-)). Allo-SCT with CCR1(-/-) donor cells significantly reduced systemic and target organ GVHD severity, and CCR1 expression on both T cells and accessory cells contributed to GVHD mortality. Significant GVL activity was preserved following CCR1(-/-) SCT, but the survival advantage diminished with increasing tumor burden. We then explored the effects of CCR1 expression on allo-specific T-cell responses. Although cytolytic effector function was maintained on a per-cell basis, T-cell proliferation and IFNgamma secretion were significantly reduced both in vivo and in vitro. T-cell function was partially dependent on interactions between CCR1 and CCL5. Collectively, these data demonstrate that CCR1 expression on donor cells contributes to the development of both GVHD and GVL, and suggest that CCR1/CCL5 receptor-ligand interactions modulate allo-specific T-cell responses occurring in this context.