[show abstract][hide abstract] ABSTRACT: The relationship between regulatory T cells (Tregs) and acute graft-versus-host disease (aGVHD) in clinical allogeneic bone marrow transplantation (BMT) recipients is not well established. We conducted a prospective analysis of peripheral blood Tregs as determined by the frequency of CD4(+)CD25(hi)FOXP3(+) lymphocytes in 215 BMT patients. Autologous BMT patients (N = 90) and allogeneic BMT patients without GVHD (N = 65) had similar Treg frequencies, whereas allogeneic patients with GVHD (N = 60) had Treg frequencies that were 40% less than those without GVHD. Treg frequencies decreased linearly with increasing grades of GVHD at onset, and correlated with eventual maximum grade of GVHD (P < .001). In addition, frequency of Tregs at onset of GVHD predicted the response to GVHD treatment (P = .003). Patients with Treg frequencies less than the median had higher nonrelapse mortality (NRM) than patients with Tregs greater than the median, but experienced equivalent relapse mortality, resulting in an inferior survival at 2 years (38% versus 63%, P = .03). Treg frequency may therefore have important prognostic value as a biomarker of aGVHD.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2010; 16(7):907-14. · 3.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Extracorporeal photopheresis (ECP), a technique that exposes isolated white blood cells to photoactivatable 8-methoxypsoralen and ultraviolet A radiation, is used clinically to treat cutaneous T-cell lymphoma and immune-mediated diseases such as graft-versus-host disease (GVHD). ECP is thought to control these diseases in part through direct induction of lymphocyte apoptosis, but its effects on the immune system beyond apoptosis remain poorly characterized. We have developed a novel method for incorporating ECP treatment into well-established and clinically relevant murine models of GVHD to examine its effects during an ongoing immune response. We demonstrate that the transfer of cells treated with ECP reverses established GVHD by increasing donor regulatory T cells and indirectly reducing the number of donor effector lymphocytes that themselves had never been exposed to psoralen and ultraviolet A radiation.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Sema4D (CD100), a member of the neuro-semaphorin family of proteins, has recently been shown to play a role in modulating certain immune responses. We tested the requirement of Sema4D expression on T cells in the induction of T cell allo-immune responses. Sema4D-/- T cells showed reduced expansion in vitro upon stimulation with allo-geneic antigen presenting cells (APCs) when compared to wild-type (wt) T cells. Similar in vitro results were observed using anti-Sema4D mAbs. Further studies demonstrated that the reduced proliferation was not due to intrinsic T cell defects, and that the cytotoxic functions were preserved. After allo-geneic bone marrow transplant (BMT), recipients of Sema4D-/- T cells showed reduced mortality and graft-versus-host disease (GVHD) target organ damage. Allo-geneic dendritic cells (DCs) cocultured with Sema4D-/- responder T cells secreted less TNF-alpha and IL-12p70 compared to wt T cells. Similar reduction of DC function was observed with anti-Sema4D mAbs. Given the preservation of CTL function we evaluated graft-versus-leukemia (GVL) responses. When BALB/c recipient mice were challenged with the P815 murine mastocytoma cell line (H2(d)) the recipients of allo-geneic Sema4D-/- B6 T cells showed a significant improvement in tumor free survival when compared to syngeneic recipients, thus demonstrating preservation of GVL, albeit of a lesser magnitude than allo-geneic wt T cells. In summary, Sema4D plays a significant role in mediating in vitro and in vivo allo-geneic responses by modulating T cell-APC interactions.
Biology of Blood and Marrow Transplantation 12/2007; 13(11):1294-1303. · 3.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sema4D (CD100) is a 150 kDa transmembrane protein member of the class IV semaphorin family that has immunomodulatory functions, and is essential for the activation and differentiation of antigen specific T cells. We investigated the effects of CD100 expression on T cells in allotransplantation. In vitro studies showed that T cells from genetically engineered CD100−/− mice expanded ten fold less than B6 wild type (wt) T cells (10800 ± 1229.9 vs. 1600 ± 258 cpm P < .01) in response to BALB/c allogeneic stimulators. We then evaluated the role of CD100 in vivo utilizing a well characterized experimental model of graft-versus-host disease (GvHD) where donor and recipient are mismatched at both major and minor histocompatibility antigens [B6 (H2b)→BALB/c (H2d)]. Recipient BALB/c animals were irradiated with 8 Gy and transplanted with 5.0 × 106 million bone marrow (BM) cells from B6 animals together with 0.5 million T cells from either B6 wild type (wt) or CD100 −/− donors. As shown in Table 1, at day 60 after transplant, mice that received CD100 −/− T cells had significantly less clinical GvHD scores and improved survival (P = .08) compared to allogeneic wt T cells. Recipients of CD100−/− T cells also demonstrated significantly reduced GvHD pathology in the intestine, liver and skin on day 60. All of BMT recipients showed complete donor engraftment. Examination of T cells in the spleen on day 14 showed that CD100 −/− T cells expanded fourfold less than wild type (P < .01). Together our data show that Sema4D is a co-stimulatory molecule that modulates T cell allogeneic responses both in vitro and in vivo and may represent a novel target for the prevention of GvHD.