RESUMEN
Interferon-gamma (IFN-gamma) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving allogeneic hematopoietic cell transplantation (allo-HCT) but promotes lethality in unirradiated and sublethally irradiated recipients. We investigated the role of IFN-gamma in GVHD in sublethally irradiated B6D2F1 recipients of B6 allo-HCT. B6D2F1 mice receiving wild-type B6 splenocytes alone died rapidly, whereas those receiving wild-type B6 splenocytes plus marrow survived long-term. Mice in both groups showed rapid elimination of host hematopoietic cells but minimal parenchymal tissue injury. However, mice receiving allo-HCT from IFN-gamma-deficient donors died rapidly regardless of whether donor marrow was given, and they exhibited severe parenchymal injury but prolonged survival of host hematopoietic cells. IFN-gamma plays a similar role in another model involving delayed B6 donor leukocyte infusion (DLI) to established mixed allogeneic (B6-->BALB/c) chimeras. IFN-gamma promotes DLI-mediated conversion from mixed to full donor chimerism while attenuating GVHD. Importantly, IFN-gamma enhances graft-versus-leukemia (GVL) effects in both models. Our data indicate that previously reported IFN-gamma-induced early mortality in allo-HCT recipients is due to augmentation of lymphohematopoietic graft-versus-host reaction (LGVHR) and can be avoided by providing an adequate source of donor hematopoietic stem/progenitor cells. Furthermore, the magnitude of GVL is correlated with the strength of LGVHR, and IFN-gamma reduces the potential of this alloreactivity to cause epithelial tissue GVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia/inmunología , Trasplante de Células Madre Hematopoyéticas , Interferón gamma/genética , Interferón gamma/inmunología , Animales , Modelos Animales de Enfermedad , Epitelio/inmunología , Epitelio/patología , Femenino , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Transfusión de Leucocitos , Linfopoyesis/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Quimera por Radiación , Trasplante Homólogo , Irradiación Corporal TotalRESUMEN
We previously found that CD8 T cells from IFN-gamma gene knockout (GKO) donors induce more severe lethal GVHD compared with CD8 T cells from wild-type (WT) donors in fully MHC-mismatched strain combinations. In this study, we investigated the mechanisms by which IFN-gamma inhibits GVHD in a parent --> F1 (B6 --> B6D2F1) allogeneic HCT (allo-HCT) model. IFN-gamma was strongly protective against GVHD in this parent --> F1 haplotype-mismatched allo-HCT model. Irradiated B6D2F1 mice that received GKO B6 CD4-depleted splenocytes developed lethal GVHD with severe lung and liver injury, whereas those receiving a similar cell population from WT B6 donors survived long term. Donor CD8 cells showed rapid activation, accelerated cell division, and reduced/delayed activation-induced cell death in allogeneic recipients in which donor cells were incapable of producing IFN-gamma. In consequence, the numbers of activated/effector (ie, CD25+, CD62L-, and CD44(high)) donor CD8 T cells in the recipients of GKO allo-HCT significantly exceeded those in mice receiving WT allo-HCT. These data show that IFN-gamma negatively regulates the CD8 T cell response by inhibiting cell division and promoting cell death and suggest that blockade of IFN-gamma could augment the severity of GVHD in patients undergoing allo-HCT.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas , Interferón gamma/inmunología , Animales , Apoptosis/fisiología , Linfocitos T CD8-positivos/fisiología , División Celular/fisiología , Femenino , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antígenos de Histocompatibilidad Menor/inmunología , Modelos Animales , Trasplante HomólogoRESUMEN
Interferon (IFN)-gamma, a potent proinflammatory cytokine produced by multiple types of cells (e.g., activated T, NK and NKT cells), plays important and complex roles in both innate and adaptive immune responses. There may be a correlation between the IFNgamma level and GVHD severity in patients receiving allogeneic hematopoietic cell transplantation. However, such a correlation may just reflect the presence of large numbers of activated T cells, and does not necessarily imply a harmful role of IFN-gamma in the pathogenesis of GVHD. There has been increasing experimental evidence that IFN-gamma is not required and may even inhibit GVHD. Paradoxically, IFN-gamma facilitates graft-versus-leukemic (GVL) effects. Thus, IFN-gamma blockade is likely deleterious in patients after allogeneic hematopoietic cell transplantation, and not beneficial as previously suggested.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia/inmunología , Trasplante de Células Madre Hematopoyéticas , Interferón gamma/inmunología , Activación de Linfocitos/inmunología , Linfocitos/inmunología , Animales , Enfermedad Injerto contra Huésped/patología , Humanos , Linfocitos/patología , Trasplante HomólogoRESUMEN
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.