Am. J. Respir. Cell Mol. Biol., Volume 25, Number 1, July, 2001 26-34

Oral Tolerance Induction by Type V Collagen Downregulates Lung Allograft Rejection

Kazuhiro Yasufuku, Kathleen M. Heidler, Patrick W. O'Donnell, Gerald N. Smith Jr., Oscar W. Cummings, Brian H. Foresman, Takehiko Fujisawa, and David S. Wilkes

Department of Surgery, Institute of Pulmonary Cancer Research, Chiba University School of Medicine, Chiba, Japan; and Departments of Medicine, Microbiology and Immunology, and Pathology, Indiana University School of Medicine, Indianapolis, Indiana

Immunization with specific proteins or peptides has been used to induce immunologic tolerance to allografts other than the lung. Recently, we have reported that the immune response to lung alloantigen also involves an immune response to type V collagen [col(V)]. The purpose of the current study was to determine if oral administration of col(V) to lung allograft recipients before transplantation downregulates acute rejection episodes. The data show that, compared with controls, col(V)-fed recipients had fewer polymorphonuclear cells and lymphocytes in allograft bronchoalveolar lavage fluid, and reduced rejection pathology. Data showing that col(V)- fed allograft recipients had diminished delayed-type hypersensitivity (DTH) responses to donor alloantigens suggest that feeding col(V) prevented allograft rejection by inducing tolerance to donor antigens. Systemic production of transforming growth factor (TGF)-, interleukin (IL)-4, or IL-10 has been reported to be a mechanism for oral tolerance-induced suppression of immune responses. Feeding col(V) induced upregulated production of TGF-, but not IL-4 or IL-10 in serum. Neutralizing TGF- recovered the DTH response to donor antigen in tolerant allograft recipients. Collectively, these data show that oral administration of col(V) is a novel approach to induce immunologic tolerance to lung allografts, and that TGF- contributed to suppression of the rejection response.

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