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.

This article has been cited by other articles:

				J. L. Bobadilla, R. B. Love, E. Jankowska-Gan, Q. Xu, L. D. Haynes, R. K. Braun, M. S. Hayney, A. Munoz del Rio, K. Meyer, D. S. Greenspan, et al. Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 660 - 668. [Abstract] [Full Text] [PDF]

				B. Mahesh, H.-S. Leong, A. McCormack, P. Sarathchandra, A. Holder, and M. L. Rose Autoantibodies to Vimentin Cause Accelerated Rejection of Cardiac Allografts Am. J. Pathol., April 1, 2007; 170(4): 1415 - 1427. [Abstract] [Full Text] [PDF]

				A. Bharat, R. C. Fields, E. P. Trulock, G. A. Patterson, and T. Mohanakumar Induction of IL-10 Suppressors in Lung Transplant Patients by CD4+25+ Regulatory T Cells through CTLA-4 Signaling J. Immunol., October 15, 2006; 177(8): 5631 - 5638. [Abstract] [Full Text] [PDF]

				D. S. Wilkes, T. M. Egan, and H. Y. Reynolds Lung Transplantation: Opportunities for Research and Clinical Advancement Am. J. Respir. Crit. Care Med., October 15, 2005; 172(8): 944 - 955. [Abstract] [Full Text] [PDF]

				A. M. Ramirez, S. Takagawa, M. Sekosan, H. A. Jaffe, J. Varga, and J. Roman Smad3 Deficiency Ameliorates Experimental Obliterative Bronchiolitis in a Heterotopic Tracheal Transplantation Model Am. J. Pathol., October 1, 2004; 165(4): 1223 - 1232. [Abstract] [Full Text] [PDF]

				T. L. Sumpter and D. S. Wilkes Role of autoimmunity in organ allograft rejection: a focus on immunity to type V collagen in the pathogenesis of lung transplant rejection Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1129 - L1139. [Abstract] [Full Text] [PDF]

				K. A. Swanson, Y. Zheng, K. M. Heidler, T. Mizobuchi, and D. S. Wilkes CDllc+ Cells Modulate Pulmonary Immune Responses by Production of Indoleamine 2,3-Dioxygenase Am. J. Respir. Cell Mol. Biol., March 1, 2004; 30(3): 311 - 318. [Abstract] [Full Text] [PDF]

				T. Mizobuchi, K. Yasufuku, Y. Zheng, M. A. Haque, K. M. Heidler, K. Woods, G. N. Smith Jr., O. W. Cummings, T. Fujisawa, J. S. Blum, et al. Differential Expression of Smad7 Transcripts Identifies the CD4+CD45RChigh Regulatory T Cells That Mediate Type V Collagen-Induced Tolerance to Lung Allografts J. Immunol., August 1, 2003; 171(3): 1140 - 1147. [Abstract] [Full Text] [PDF]

				E. V. Fedoseyeva, K. Kishimoto, H. K. Rolls, B. M.-W. Illigens, V. M. Dong, A. Valujskikh, P. S. Heeger, M. H. Sayegh, and G. Benichou Modulation of Tissue-Specific Immune Response to Cardiac Myosin Can Prolong Survival of Allogeneic Heart Transplants J. Immunol., August 1, 2002; 169(3): 1168 - 1174. [Abstract] [Full Text] [PDF]

				M. A. Haque, T. Mizobuchi, K. Yasufuku, T. Fujisawa, R. R. Brutkiewicz, Y. Zheng, K. Woods, G. N. Smith, O. W. Cummings, K. M. Heidler, et al. Evidence for Immune Responses to a Self-Antigen in Lung Transplantation: Role of Type V Collagen-Specific T Cells in the Pathogenesis of Lung Allograft Rejection J. Immunol., August 1, 2002; 169(3): 1542 - 1549. [Abstract] [Full Text] [PDF]