Inhibition of donor-derived T cells trafficking into target organs by FTY720 during acute graft-versus-host disease in small bowel transplantation (original) (raw)
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Transplantation Proceedings, 2006
Aims. The potency of immunosuppression is a critical factor in small bowel transplantation (SBTx). FTY720 altered lymphocyte trafficking and prevented the donor T cells from migrating into target organs, resulting in the prolongation of recipient survival in acute graft-versus-host disease (GVHD) of SBTx. However, the effect of FTY720 on donor T cells in the chronic phase of GVHD following SBTx remains unclear. Methods. Heterotopic SBTx was performed in a WF-to-F1 (WF ϫ ACI) rat combination. Recipients were given FTY720 for 14 days after SBTx. The subpopulations of donor-derived T cells and the cytokine production in the target tissues were evaluated on postoperative day 150. Results. FTY720 treatment significantly prolonged recipient survival over 150 days without any clinical signs of GVHD. The numbers of donor-derived CD4 ϩ and CD8 ϩ T cells in the peripheral blood, mesenteric lymph nodes, and Peyer's patches of recipients were maintained at low levels on postoperative 150, which were almost similar to the levels on postoperative day 14. In the host lamina propria, however, a significant higher number of donor T cells (CD4 ϩ , 18.4 Ϯ 4.3 ϫ 10 4 ; CD8 ϩ , 13.9 Ϯ 3.6 ϫ 10 4 ) were still observed on postoperative day 150. Production of interferon-␥ was significantly reduced in target tissues by FTY720 treatment both in the acute and chronic phase. However, interleukin-4 and interleukin-10 production, which was significantly higher on day 14, returned to the level of naive rats in the chronic phase. Conclusions. A 14-day treatment of FTY720 induced tolerance in our SBTx model. Down-regulation of both Th1 and Th2 immune response was observed in the chronic phase.
European Journal of Immunology, 2007
FTY720 is a novel immunosuppressant that improves the outcomes after solid organ and bone marrow transplantation (BMT) due to the sequestration of T cells into LN. We tested the hypothesis that the sequestration of donor T cells in LN by FTY720 would enhance their interaction with host APC, thus causing a greater degree of activationinduced apoptosis of alloreactive T cells, and thereby resulting in a reduction of graftvs.-host disease (GVHD). The short-term administration of FTY720 improved the recipient survival after allogeneic BMT. FTY720 treatment facilitated a rapid contraction of the donor T cell pool in association with an increased degree of apoptosis of donor T cells. The donor T cell reactivity to host alloantigens was diminished in host's LN and adoptive transfer of donor T cells isolated from LN of FTY720-treated recipients of allogeneic BMT induced less severe GVHD in secondary recipients than the transfer from controls. Caspase-dependent apoptosis was involved in this mechanism because FTY720-induced protection was abrogated when a pan-caspase inhibitor was administered. These findings thus demonstrate the presence of a novel mechanism by which FTY720 modulates the allogeneic T cell responses: namely, by the induction of activation-induced apoptosis of alloreactive T cells in LN.
Journal of Clinical Investigation, 2003
Graft-versus-host disease (GvHD) mediated by donor T cells recognizing host alloantigens is associated with beneficial graft-versus-tumor effects in recipients of allogeneic hematopoietic cell transplants. Since leukemias and lymphomas reside largely within the lymphohematopoietic system, we have proposed that the desired graft-versus-leukemia or graft-versus-lymphoma effect can be separated from the complication of GvHD by confinement of the graft-versus-host alloresponse to the lymphohematopoietic tissues. Since the new sphingosine-1-phosphate receptor agonist immunosuppressive drug FTY720 leads to trapping of T cells in secondary lymphoid tissues, we evaluated the possibility that this drug could diminish GvHD, a disease involving epithelial target tissues, while permitting a beneficial alloresponse to take place within the lymphohematopoietic system, leading to graft-versus-lymphoma effects. We demonstrate here that FTY720 markedly reduces GvHD in a clinically relevant, haploidentical strain combination, while permitting antitumor effects against a T cell lymphoma of unshared host MHC haplotype to proceed unhindered. These results establish a potential new immunotherapeutic approach to separating graft-versus-leukemia effects from GvHD.
Journal of Clinical Investigation, 1989
In these studies, the role of T helper and T cytotoxic cells in generating intestinal graft-vs.-host disease (GVHD) was examined. Treatment of C57BL/6J (B6) splenocytes with L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) selectively removes natural killer cells, cytotoxic T lymphocyte (CIL) precursors, and the capacity to cause lethal GVHD in irradiated B6xDBA/2 Fl (B6D2Fl) mice while preserving T helper cell function. Neither control nor Leu-Leu-OMe-treated DBA/2 donor spleen and bone marrow cells were found to induce lethal GVHD in B6D2F1 recipients. However, extensive colonic GVHD developed in B6D2F1 recipients of DBA/2 bone marrow and spleen cells. Enteropathic GVHD in DBA/2 -* B6D2F1 mice was reduced in severity after anti-L3T4 + C treatment of donor cells, and was eliminated by anti-Thyl.2 + C or the combination of anti-L3T4 and anti-Lyt2 + C treatment of the donor cell inoculum. However, neither anti-Lyt2 + C, Leu-Leu-OMe, nor anti-Lyt2 + C and Leu-Leu-OMe treatment of donor cells significantly decreased severity of gut GVHD. Leu-Leu-OMe treatment of DBA/2 or B6 SpC was comparably effective in preventing in vitro or in vivo generation of B6D2Fl-specific CiL. These findings, therefore, demonstrate that histologically severe enteropathic GVHD does not require participation of CIL and is not always associated with high mortality rates.
Journal of Experimental Medicine, 2004
Glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) is a member of the tumor necrosis factor receptor (TNFR) family that is expressed at low levels on unstimulated T cells, B cells, and macrophages. Upon activation, CD4 ϩ and CD8 ϩ T cells up-regulate GITR expression, whereas immunoregulatory T cells constitutively express high levels of GITR. Here, we show that GITR may regulate alloreactive responses during graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Using a BMT model with major histocompatibility complex class I and class II disparity, we demonstrate that GITR stimulation in vitro and in vivo enhances alloreactive CD8 ϩ CD25 Ϫ T cell proliferation, whereas it decreases alloreactive CD4 ϩ CD25 Ϫ proliferation. Allo-stimulated CD4 ϩ CD25 Ϫ cells show increased apoptosis upon GITR stimulation that is dependent on the Fas-FasL pathway. Recipients of an allograft containing CD8 ϩ CD25 Ϫ donor T cells had increased GVHD morbidity and mortality in the presence of GITR-activating antibody (Ab). Conversely, recipients of an allograft with CD4 ϩ CD25 Ϫ T cells showed a significant decrease in GVHD when treated with a GITRactivating Ab. Our findings indicate that GITR has opposite effects on the regulation of alloreactive CD4 ϩ and CD8 ϩ T cells.
Transplant Immunology
Graft-versus-host disease (GVHD) is a frequent complication following allogeneic hematopoietic stem cell transplantation (HSCT) with current therapies limited to general immunosuppression. Humanized mouse models of GVHD are emerging as valuable intermediaries to allow translation of findings from allogeneic mouse models to humans to prevent and treat this disease, but such models require further characterization. In this study, humanized mice were generated by injecting immunodeficient non-obese diabetic severe combined immunodeficiency interleukin (IL)-2 receptor γ common chain null (NSG) mice with human peripheral blood mononuclear cells (hPBMCs). Clinical GVHD development was assessed using established scoring criteria (weight loss, posture, activity, fur texture and skin integrity). Differences between humanized NSG mice that developed clinical or subclinical GVHD were then compared. Both groups of mice demonstrated similar frequencies of human leukocyte engraftment. In contrast, mice that developed clinical GVHD demonstrated increased histological damage compared to mice with subclinical GVHD. Furthermore, mice with clinical GVHD exhibited increases in the splenic human CD4 + :CD8 + T cell ratio, serum human interferon (IFN)-γ and intestinal human IL-17 expression compared to mice with subclinical GVHD. These cellular and molecular changes could be used as potential markers of disease progression in this preclinical model. This study also provides further insights into GVHD development which may be relevant to human HSCT recipients.
Long-term effect of FTY720 on lymphocyte count and islet allograft survival in mice
Microsurgery, 2007
This study was performed to observe the long-term effect of FTY720 on lymphocyte count change and islet allograft survival. Diabetic C57BL/6 mice were given FTY720 (group 1, 0.5 mg/kg/day; group 2, 1.0 mg/kg/day) or its vehicle (group 3, controls) after transplantation. Median graft survival time was prolonged in a dose-dependent manner (group 1, 84.5 days; group 2, >100 days, and group 3, 10 days, P < 0.01). Peripheral blood lymphocytes in groups 1 and 2 decreased to 23.81% and 12.59% compared with control group after FTY720 treatment. Lymphocytes from mesenteric lymph nodes and axillary nodes in groups 1 and 2 significantly increased on day 5, but decreased on day 14. Lymphocyte infiltration to the graft site was attenuated in groups 1 and 2. In conclusion, continuous FTY720 administration can induce and maintain lymphopenia, and inhibit lymphocytes from infiltrating the graft site so as to prolong islet allograft survival in mice. © 2007 Wiley-Liss, Inc. Microsurgery 2007.
Blood, 2006
The α4β7 integrin plays a central role in the homing of T cells to the gut. We hypothesized that absence of the β7 subunit would result in a reduction of intestinal graft-versus-host disease (GVHD) and an improvement in overall GVHD morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT). Analysis of alloreactive β7-/- T cells showed intact activation, proliferation, cytokine production, and cytotoxicity. However, recipients of β7-/- donor T cells in murine HSCT models experienced less GVHD morbidity and mortality than recipients of wild-type (WT) T cells, associated with a decrease in donor T-cell infiltration of the liver and intestine and with an overall significant decrease in hepatic and intestinal GVHD. In graft-versus-tumor (GVT) experiments, we demonstrated intact or even enhanced GVT activity of β7-/- donor T cells. In conclusion, β7-/- donor T cells caused less GVHD morbidity and mortality than WT donor T cells because of selectively decreas...