Induction of oral tolerance in a murine model of chronic graft versus host disease ameliorates disease manifestation

A. Nagler, M. Pines, U. Abadi, Q. Pappo, M. Zeira, N. Roy Chowdhurv, J. Rov Chowdhury, Y. Llan

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic graft versus host disease (cGVHD) is an autoimmune-like disorder resulting in skin manifestations resembling scleroderma. Induction of immunological hyporesponsiveness to orally administered antigens have been recently shown to suppress autoimmunity in several animal models. We studied the feasibility of inducing oral tolerance and ameliorate disease manifestation in a cGVHD mice model. cGVHD was induced by administration of splenocytes (25xl06) from B10.D2 to sublethaly irradiated (600Gy) Balb/c mice, across minor histocompatibility antigens (H-2 , mlsb). In this model cGVHD is manifested by scleroderma like skin lessions, fibrös is, increase in skin collagen, and loss of subdermal fat, weight loss, and severe liver inflammation. Oral tolerance was induced by feeding B10.D2 donor mice with Balb/c recipient splenocyte protein extract at a dose of 50u,g/mice for 11 days prior to transplantation. Induction of tolerance was documented by significant reduction in the MLR response of tolerated versus non tolerated effector B10.12 splenocytes against Balb/c stimulators, respectively (24,000 versus 8,000 cpm) (n=3) (p<0.01). Induction of oral tolerance prevented weight loss and resulted in significant reduction in skin collagen content and gene expression evaluated by immunohistochemistry and in situ hybridization using collagen a 1(1) probe. It also prevented dermal thickening and loss of subdermal fat. Liver biopsies disclosed marked reduction in inflammatory response. Serum IL-10 levels were significantly higher in the tolerized mice (108.5 versus 46.5 pg/ml) while IFN-ct, IL-2 and TNF-a were significantly lower than the controls 10,11 a 2.5pg/ml vs 75.3, 22 a and I6.5pg/ml, respectively (n=3) (p<0.005). In summary, induction of oral tolerance resulted in a shift from Th 1 proinflammatory to a Th2 anti-inflammatory cytokine profile, downregulating the immune response and ameliorating cGVHD.

Original languageEnglish
Pages (from-to)777
Number of pages1
JournalExperimental Hematology
Volume26
Issue number8
StatePublished - 1998
Externally publishedYes

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