Immunoregulation of GVHD by triggering the innate immune system with CpG.
ABSTRACT Stimulation of Toll-like receptors by oligodeoxynucleotide sequences containing a CpG motif provides signals capable of triggering the innate and adaptive immune systems, thereby leading either to stimulation or suppression of immunoreactivities. Similar immunoregulatory capabilities are necessary for achieving the fine balance between engraftment and graft-versus-host disease required in the setup of allogeneic cell therapy. Ligation of CpG to its Toll-like receptors can be accomplished by treatment of the host or pretransplant treatment of the donor in vivo. These different strategies are presented in this review, which summarizes the attempts to maximize beneficial alloreactivity against malignant or other undesirable host cells, while controlling graft-versus-host disease.
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ABSTRACT: T cell depletion prevents graft-versus-host disease (GVHD) but also removes T cell-mediated support of hematopoietic cell engraftment. A chimeric molecule composed of IL-2 and caspase-3 (IL2-cas) has been evaluated as a therapeutic modality for GVHD and selective ex vivo depletion of host-reactive T cells. IL2-cas does not affect hematopoietic cell engraftment and significantly reduces the clinical and histological severity of GVHD. Early administration of IL2-cas reduced the lethal outcome of haploidentical transplants, and survivor mice displayed markedly elevated levels of X-linked forkhead/winged helix (FoxP3(+); 50%) and CD25(+)FoxP3(+) T cells (35%) in the lymph nodes. The chimeric molecule induces in vitro apoptosis in both CD4(+)CD25(-) and CD4(+)CD25(+) subsets of lymphocytes from alloimmunized mice, and stimulates proliferation of cells with highest levels of CD25 expression. Adoptive transfer of IL2-cas-pretreated viable splenocytes into sublethally irradiated haploidentical recipients resulted in 60% survival after a lethal challenge with lipopolysaccharide, which is associated with elevated fractions of CD25(high)FoxP3(+) T cells in the lymph nodes of survivors. These data demonstrate that ex vivo purging of host-presensitized lymphocytes is effectively achieved with IL2-cas, and that IL-2-targeted apoptotic therapy reduces GVHD severity in vivo. Both approaches promote survival in lethal models of haploidentical GVHD. The mechanism of protection includes direct killing of GVHD effectors, prevention of transition to effector/memory T cells, and induction of regulatory T cell proliferation, which becomes the dominant subset under conditions of homeostatic expansion.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2012; 18(4):523-35. · 3.15 Impact Factor
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ABSTRACT: Our understanding of graft-versus-host disease (GVHD) has mostly focused on the role of adaptive immunity in mediating host-recipient genetic disparity in the proinflammatory milieu. These experimental models rarely address the unique biology of GVHD whereby it targets mainly epithelial compartments of the intestine, skin, and liver. Recent discoveries of the role of the microbiota in health and disease have reinvigorated questions about how the innate immunity contributes to the pathogenesis of GVHD and perhaps explains its tissue tropism. In this review, we discuss findings indicating the potential role of pattern-recognition receptors of the innate immune system in mediating GVHD and present evidence that shows how the microbiota interact with the host to shape health and disease. These findings support a reevaluation of our current clinical practice and encourage further studies of the potential critical role of the gut microbiota in hematopoietic stem cell transplant which may lead to novel preventive and therapeutic targets against GVHD.Leukemia & lymphoma 06/2011; 52(10):1844-56. · 2.61 Impact Factor