HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smith, X. G. Articles by Bradley, J. A. Search for Related Content PubMed PubMed Citation Articles by Smith, X. G. Articles by Bradley, J. A. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Heart Transplantation

Selective Blockade of IL-15 by Soluble IL-15 Receptor -Chain Enhances Cardiac Allograft Survival¹

Xin G. Smith^*, Eleanor M. Bolton^*, Holger Ruchatz, Xiao-quing Wei, Foo Y. Liew and J. Andrew Bradley^2,*

^* Department of Surgery, University of Cambridge, Cambridge, United Kingdom; and Department of Immunology and Bacteriology, University of Glasgow, Glasgow, United Kingdom

IL-15 is a T cell growth factor that shares many functional similarities with IL-2 and has recently been shown to be present in tissue and organ allografts, leading to speculation that IL-15 may contribute to graft rejection. Here, we report on the in vivo use of an IL-15 antagonist, a soluble fragment of the murine IL-15R -chain, to investigate the contribution of IL-15 to the rejection of fully vascularized cardiac allografts in a mouse experimental model. Administration of soluble fragment of the murine IL-15R -chain (sIL-15R) to CBA/Ca (H-2^k) recipients for 10 days completely prevented rejection of minor histocompatibility complex-mismatched B10.BR (H-2^k) heart grafts (median survival time (MST) of >100 days vs MST of 10 days for control recipients) and led to a state of donor-specific immunologic tolerance. Treatment of CBA/Ca recipients with sIL-15R alone had only a modest effect on the survival of fully MHC-mismatched BALB/c (H-2^d) heart grafts. However, administration of sIL-15R together with a single dose of a nondepleting anti-CD4 mAb (YTS 177.9) delayed mononuclear cell infiltration of the grafts and markedly prolonged graft survival (MST of 60 days vs MST of 20 days for treatment with anti-CD4 alone). Prolonged graft survival was accompanied in vitro by reduced proliferation and IFN- production by spleen cells, whereas CTL and alloantibody levels were similar to those in animals given anti-CD4 mAb alone. These findings demonstrate that IL-15 plays an important role in the rejection of a vascularized organ allograft and that antagonists to IL-15 may be of therapeutic value in preventing allograft rejection.

This article has been cited by other articles:

				C. Bergamaschi, M. Rosati, R. Jalah, A. Valentin, V. Kulkarni, C. Alicea, G.-M. Zhang, V. Patel, B. K. Felber, and G. N. Pavlakis Intracellular Interaction of Interleukin-15 with Its Receptor {alpha} during Production Leads to Mutual Stabilization and Increased Bioactivity J. Biol. Chem., February 15, 2008; 283(7): 4189 - 4199. [Abstract] [Full Text] [PDF]

				T. A. Stoklasek, K. S. Schluns, and L. Lefrancois Combined IL-15/IL-15R{alpha} Immunotherapy Maximizes IL-15 Activity In Vivo J. Immunol., November 1, 2006; 177(9): 6072 - 6080. [Abstract] [Full Text] [PDF]

				I. Lorenzen, A. J. Dingley, Y. Jacques, and J. Grotzinger The Structure of the Interleukin-15{alpha} Receptor and Its Implications for Ligand Binding J. Biol. Chem., March 10, 2006; 281(10): 6642 - 6647. [Abstract] [Full Text] [PDF]

				E. Mortier, A. Quemener, P. Vusio, I. Lorenzen, Y. Boublik, J. Grotzinger, A. Plet, and Y. Jacques Soluble Interleukin-15 Receptor {alpha} (IL-15R{alpha})-sushi as a Selective and Potent Agonist of IL-15 Action through IL-15Rbeta/{gamma}: HYPERAGONIST IL-15{middle dot}IL-15R{alpha} FUSION PROTEINS J. Biol. Chem., January 20, 2006; 281(3): 1612 - 1619. [Abstract] [Full Text] [PDF]

				R. Ruckert, K. Brandt, A. Braun, H.-G. Hoymann, U. Herz, V. Budagian, H. Durkop, H. Renz, and S. Bulfone-Paus Blocking IL-15 Prevents the Induction of Allergen-Specific T Cells and Allergic Inflammation In Vivo J. Immunol., May 1, 2005; 174(9): 5507 - 5515. [Abstract] [Full Text] [PDF]

				B. W. Blaser, S. Roychowdhury, D. J. Kim, N. R. Schwind, D. Bhatt, W. Yuan, D. F. Kusewitt, A. K. Ferketich, M. A. Caligiuri, and M. Guimond Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease Blood, January 15, 2005; 105(2): 894 - 901. [Abstract] [Full Text] [PDF]

				V. Budagian, E. Bulanova, Z. Orinska, A. Ludwig, S. Rose-John, P. Saftig, E. C. Borden, and S. Bulfone-Paus Natural Soluble Interleukin-15R{alpha} Is Generated by Cleavage That Involves the Tumor Necrosis Factor-{alpha}-converting Enzyme (TACE/ADAM17) J. Biol. Chem., September 24, 2004; 279(39): 40368 - 40375. [Abstract] [Full Text] [PDF]

				E. Mortier, J. Bernard, A. Plet, and Y. Jacques Natural, Proteolytic Release of a Soluble Form of Human IL-15 Receptor {alpha}-Chain That Behaves as a Specific, High Affinity IL-15 Antagonist J. Immunol., August 1, 2004; 173(3): 1681 - 1688. [Abstract] [Full Text] [PDF]

				A. A. Ashkar and K. L. Rosenthal Interleukin-15 and Natural Killer and NKT Cells Play a Critical Role in Innate Protection against Genital Herpes Simplex Virus Type 2 Infection J. Virol., September 15, 2003; 77(18): 10168 - 10171. [Abstract] [Full Text] [PDF]

				E. Bulanova, V. Budagian, Z. Orinska, H. Krause, R. Paus, and S. Bulfone-Paus Mast Cells Express Novel Functional IL-15 Receptor {alpha} Isoforms J. Immunol., May 15, 2003; 170(10): 5045 - 5055. [Abstract] [Full Text] [PDF]

				N. Ohta, T. Hiroi, M.-N. Kweon, N. Kinoshita, M. H. Jang, T. Mashimo, J.-I. Miyazaki, and H. Kiyono IL-15-Dependent Activation-Induced Cell Death-Resistant Th1 Type CD8{alpha}{beta}+NK1.1+ T Cells for the Development of Small Intestinal Inflammation J. Immunol., July 1, 2002; 169(1): 460 - 468. [Abstract] [Full Text] [PDF]

				I. A. Khan, M. Moretto, X.-q. Wei, M. Williams, J. D. Schwartzman, and F. Y. Liew Treatment with Soluble Interleukin-15R{alpha} Exacerbates Intracellular Parasitic Infection by Blocking the Development of Memory CD8+ T Cell Response J. Exp. Med., June 3, 2002; 195(11): 1463 - 1470. [Abstract] [Full Text] [PDF]

				T. R. Jones, J. Ha, M. A. Williams, A. B. Adams, M. M. Durham, P. A. Rees, S. R. Cowan, T. C. Pearson, and C. P. Larsen The Role of the IL-2 Pathway in Costimulation Blockade-Resistant Rejection of Allografts J. Immunol., February 1, 2002; 168(3): 1123 - 1130. [Abstract] [Full Text] [PDF]

				S. Ferrari-Lacraz, X. X. Zheng, Y. S. Kim, Y. Li, W. Maslinski, X. C. Li, and T. B. Strom An Antagonist IL-15/Fc Protein Prevents Costimulation Blockade-Resistant Rejection J. Immunol., September 15, 2001; 167(6): 3478 - 3485. [Abstract] [Full Text] [PDF]

				X.-q. Wei, M. Orchardson, J. A. Gracie, B. P. Leung, B.-m. Gao, H. Guan, W. Niedbala, G. K. Paterson, I. B. McInnes, and F. Y. Liew The Sushi Domain of Soluble IL-15 Receptor {{alpha}} Is Essential for Binding IL-15 and Inhibiting Inflammatory and Allogenic Responses In Vitro and In Vivo J. Immunol., July 1, 2001; 167(1): 277 - 282. [Abstract] [Full Text] [PDF]