Induction of oral tolerance in bone marrow transplantation recipients suppresses graft-versus-host disease in a semiallogeneic mouse model

Abstract

Summary:Graft-versus-host disease (GVHD) is the major obstacle for successful allogeneic stem cell transplantation (SCT). Morbidity and mortality are high, and novel therapeutic strategies are required. Current therapy, which is based mainly on immunosuppression, is associated with a high degree of complications. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of chronic GVHD (cGVHD) in a murine model. The aim of the present study was to evaluate whether it is possible to induce tolerance and to alleviate GVHD in a semiallogeneic transplantation model in mice. GVHD was generated by infusing 2 Â 10 7 splenocytes from C57BL/6 donor mice into (C57BL/6 Â Balb/c)F1 recipient mice, which received 7 Gy 60 Co total body irradiation (TBI) prior to transplantation. Oral tolerance was induced by feeding recipient F1 mice with five oral doses of proteins, 50 lg/mouse, extracted from C57BL/6 splenocytes on alternate days following transplantation. In vitro mixed lymphocyte reaction (MLR) from tolerized and nontolerized mice was performed. Recipient mice were followed for chimerism, and for clinical and histological parameters of GVHD. Induction of tolerance was documented by a significant reduction in MLR response of tolerated vs nontolerated splenocytes. A significant alleviation of the clinical and pathological manifestation of GVHD was observed in the liver, small bowel, and skin. Tolerance induction did not jeopardize engraftment. These results may constitute a step towards reducing the frequency of GVHD via manipulation of the immune system. Bone Marrow Transplantation (2003) 32, 363-369. doi:10.1038/sj.bmt.1704145 Keywords: oral tolerance; immune tolerance; GVHD Graft-versus-host disease (GVHD) is a multi-organ disorder that develops following stem cell transplantation (SCT). 1 The pathogenesis involves recognition of alloreactive antigens, activation of T cells, as well as other immunocompetent effector cells, and tissue destruction. 2 Oral tolerance has been shown to be effective in various experimental models of immune mediated disorders. 3 Feeding small doses of the antigen has been reported to induce tolerance by generation of negative immunoregulatory cells, while administering higher doses tends to bring about clonal inactivation or deletion. 4 We have previously shown that induction of oral tolerance towards recipient splenocytes in bone marrow transplant donors, prior to bone marrow transplantation (BMT), can prevent the development of graft-versus-host inflammatory immune response. 5 We used the mouse model of chronic GVHD (cGVHD), which involved transplantation of B10.D2 splenocytes into sublethally irradiated BALB/c mice. These mouse strains are identical at MHC gene (H-2 d ) loci, but differ by their multiple minor histocompatibility antigens. Intravenous infusion of splenocytes from B10.D2 into BALB/c mice, induces cGVHD manifested by scleroderma-like skin lesions, an increase in skin collagen, thickening of the dermis, and a loss of subd...

Clinical molecular imaging in intestinal graft-versus-host disease: mapping of disease activity, prediction, and monitoring of treatment efficiency by positron emission tomography

“…38 While some authors have described a predominant inflammation of the colon in their experimental models, 39 others have reported inflammation of both the large and small bowel, 40 or mainly of the small bowel. 41 Differences were not only related to the experimental models used, they also varied between different investigators using the same donor and recipient strains. These differences imply that epigenetic factors such as housing conditions and in consequence differences in microbial colonization could have an influence on GVHD manifestation.…”

Oral Combined Therapy with Probiotics and Alloantigen Induces B Cell–Dependent Long-Lasting Specific Tolerance

“…Although promising, the clinical application of both protocols, oral tolerance induction (12) and probiotic treatment (30), cannot be used in transplanted patients. Once the conditioning regimen alters the intestinal epithelial barrier, these patients require special attention regarding their diet.…”

“…Far from being just a matter of hyporesponsiveness, oral tolerance is an active immunologic event influenced by numerous factors such as Ag dose, microbiota, and costimulatory molecules, resulting from multiple mechanisms of action (6). Induction of oral tolerance has been shown to be effective in various experimental models of immune disorders (7)(8)(9) including GVHD (10)(11)(12). In fact, Nagler et al (12) demonstrated that it is possible to alleviate acute GVHD (aGVHD) severity by the induction of oral tolerance in the recipient, although the maintenance of the GVL effect was not addressed in that study.…”

Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model

“…[17][18][19] Alternatively, restoring T cells after transplantation has been suggested as a valuable option to prevent the side effects of T cell depletion. 20 Other experimental approaches to reduce GVHD, such as induction of oral tolerance 21 or treatment with donor regulatory T cells, 22 dendritic cells 23 and NK cells, 24 are currently under investigation as well.…”