Oral tolerization ameliorates liver disorders associated with chronic graft versus host disease in mice

Abstract

In chronic graft versus host disease (cGVHD), an immune attack by transplanted donor lymphocytes results in damage of host target organs. A disbalance between proinflammatory (Th1) and anti-inflammatory cytokines (Th2) plays an important role in the pathogenesis. Immune hyporesponsiveness induced by oral antigen administration has been shown to suppress autoimmunity. We evaluated the efficacy of oral tolerization in preventing cGVHD in a mouse model. cGVHD was generated by infusing 2.5 ؋ 10 7 splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ in minor histocompatibility antigens. The transplantation resulted in cGVHD, with characteristic hepatic and small bowel inflammation, and increased skin collagen content and fibrosis.

Extracorporeal photopheresis reduces the number of mononuclear cells that produce pro‐inflammatory cytokines, when tested ex‐vivo

“…Anti TNFa antibodies have been used in the prevention of cutaneous and gastrointestinal lesions during aGvHD [21]. Transplanted mice, whose cGvHD was tolerated, 2 demonstrated statistical reductions in TNFa and IFNc levels [22].…”

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

“…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.…”

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

“…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.…”

“…Tolerance was documented by a significant reduction in MLR response of donor lymphocytes toward recipient splenocytes, and by prevention of the inflammatory immune response, which in turn resulted in the prevention of skin, small bowel, and liver manifestations of cGVHD. 5 However, clinical application of this method would require inducing tolerance in the presence of pre-existing disease, as well as immunomodulating the recipient, rather than the donor. Subsequently, we used a similar strategy in a cGVHD model, in which Balb/C mice were fed with Balb/C splenocyte homogenate following B10D2 into Balb/C transplantation.…”

“…6,7 Feeding donor mice homogenates of recipient splenocytes before transplantation prevented the clinical and microscopic manifestations of cGVHD. 5 In addition, using the same cGVHD model, we have recently shown the possibility of inducing tolerance in recipients towards their pre transplant antigens. 8 Transplantation resulted in cGVHD with characteristic scleroderma-like cutaneous fibrosis, increased skin collagen content, and decreased body weight, along with hepatic and small bowel inflammation.…”