Enhanced immunological tolerance against allograft rejection by oral administration of allogeneic antigen linked to cholera toxin B subunit.
A single oral intragastric administration of cholera toxin B subunit (CTB) conjugated to allogeneic thymocytes (ATC, 4 x 10(7) cells) under conditions allowing the CTB to bind the complex to GM1 ganglioside receptors was shown to be efficacious in inducing peripheral T cell tolerance associated with significant suppression of both primary and secondary accelerated rejection of heart allografts when tested in mice. Allogeneic in vivo delayed-type hypersensitivity (DTH), in vitro cytotoxicity responses, and mixed lymphocyte reactions (MLR) by T cells from mesenteric lymph nodes (MLN), popliteal lymph nodes (PLN), and spleen were significantly reduced in mice treated with the CTB-ATC conjugate, as were also the numbers of cells in these organs producing IL-2, IFN-gamma, or IL-4. In contrast, a marked increase in the production of IL-4 in Peyer's patches (PP) and of TGF-beta(1) in PLN was observed. The suppressive potential of T cells from PP and/or MLN after oral treatment with CTB-ATC was further evident by intraperitoneal transfer of such cells from CTB-ATC-treated animals to primed recipients, which led to marked suppression of both allogen-specific DTH and MLR responses. A critical role for PP in inducing peripheral tolerance after oral CTB-ATC treatment was indicated by the absence of tolerance induction in animals whose PP had been destroyed before treatment with CTB-ATC. The results indicate that the protection against allograft rejection by oral treatment with CTB-ATC is mediated by T cells and associated with a strong induction of IL-4 production at mucosal sites and TGF-beta(1) at the effector sites.
Sun
J B
JB
Department of Medical Microbiology and Immunology, Göteborg University, Göteborg, S-413 46, Sweden. Jia-Bin.Sun@microbio.gu.se
Li
B L
BL
Czerkinsky
C
C
Holmgren
J
J
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000284:Administration, Oral; D000818:Animals; D002772:Cholera Toxin / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance / Q000502:physiology*; D007371:Interferon-gamma / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D007519:Isoantigens / Q000008:administration & dosage; D008198:Lymph Nodes / Q000737:chemistry; D007959:Lymphocyte Culture Test, Mixed; D008643:Mesentery / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D010581:Peyer's Patches / Q000737:chemistry; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000276:Adjuvants, Immunologic; D007519:Isoantigens; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4; D007371:Interferon-gamma; D002772:Cholera Toxin