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Type V Collagen-Induced Oral Tolerance Plus Low-Dose Cyclosporine Prevents Rejection of MHC Class I and II Incompatible Lung Allografts¹

Yoshito Yamada^*,, Yasuo Sekine, Shigetoshi Yoshida, Kazuhiro Yasufuku, Irina Petrache^*,, Heather L. Benson^*,, David D. Brand, Ichiro Yoshino and David S. Wilkes^2,*,

^* Departments of Medicine, Microbiology, and Immunology, and Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; Departments of Medicine, Biochemistry, and Molecular Biology, and Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202; and Research Service, Veterans Affairs Medical Center, Memphis, TN 38104

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 (RT1ⁿ)) 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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL081350, HL60797, and HL/Al67177 (to D.S.W.); National Institutes of Health RO1 Grant HL090950 (to I.P.); Department of Veterans Affairs Research Grant (to D.B.B.); and grants-in-aid for science research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (15591466 to Y.S. and 19591612 to S.Y.).

² Address correspondence and reprint requests to Dr. David S. Wilkes, Center for Immunobiology, Indiana University School of Medicine, 635 Barnhill Drive, Van Nuys Medical Science Building MS224, Indianapolis, IN 46202. E-mail address: dwilkes{at}iupui.edu

³ Abbreviations used in this paper: BOS, bronchiolitis obliterans syndrome; AM, alveolar macrophage; BAL, bronchoalveolar lavage; BN, Brown Norway; col(V), type V collagen; CsA, cyclosporine; Treg, regulatory T cell; WKY, Wistar Kyoto.

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The JI 2009 183: 1-2. [Full Text]