Type V collagen-induced oral tolerance plus low-dose cyclosporine prevents rejection of MHC class I and II incompatible lung allografts.
Autoimmunity to type V collagen (col(V)) is a major risk factor for lung allograft rejection. Although col(V)-induced oral tolerance abrogates rejection of minor histoincompatible lung transplants, its ability to prevent rejection of fully MHC incompatible lung allografts is unknown. Rat lung allografts fully incompatible at MHC class I and II loci (Brown Norway (RT1(n))) were transplanted into untreated Wistar Kyoto rat recipients (WKY, RT1(l)), or WKY rats were fed col(V) pretransplantation. To determine whether col(V) enhanced cyclosporine (CsA)-mediated immune suppression, WKY rats were treated with low-dose CsA (5 mg/kg), posttransplant, or oral col(V) plus CsA. The data showed that in contrast to col(V) or CsA, col(V) plus low-dose CsA significantly prevented rejection pathology, down-regulated alloantigen-induced production of IFN-gamma and IL-17A, and suppressed chemotaxis for lung macrophages in allograft bronchoalveolar lavage fluid that was associated with lower local levels of MCP-1 (CCL2). Col(V) plus CsA was associated with alloantigen-induced expression of IL-10 in mediastinal lymph node or splenic T cells, intragraft expression of IL-10 and Foxp3 in perivascular and peribronchiolar mononuclear cells, and constitutive production of IL-10 from allograft alveolar macrophages. These data demonstrate that col(V) enhances low-dose CsA-mediated immune suppression, and suggest a role for oral col(V) in immune modulation in lung transplantation.
Yamada
Yoshito
Y
Department of Medicine, Center for Immunobiology, Indiana University School of Medicine, Indianapolis, 46202, USA.
Sekine
Yasuo
Y
Yoshida
Shigetoshi
S
Yasufuku
Kazuhiro
K
Petrache
Irina
I
Benson
Heather L
HL
Brand
David D
DD
Yoshino
Ichiro
I
Wilkes
David S
DS
D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D024062:Collagen Type V / Q000276:immunology* / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use*; D004306:Dose-Response Relationship, Immunologic; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006649:Histocompatibility Antigens / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006650:Histocompatibility Testing; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016040:Lung Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011921:Rats, Inbred WKY; D023001:Transplantation Tolerance / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D024062:Collagen Type V; D006649:Histocompatibility Antigens; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; C038353:histocompatibility antigens RT, rat; D016572:Cyclosporine