The Role of MIG/CXCL9 in Cardiac Allograft Vasculopathy

James Yun

Michael Fischbein

David Whiting

Yoshihito Irie

Hillel Laks+2 authors

From the Division of Cardiothoracic Surgery,^{Department of Surgery, and the Departments of Pathology and Laboratory Medicine}^{and Medicine,}^{University of California at Los Angeles, Los Angeles, California}

Accepted 2002 Jun 28.

Abstract

T lymphocytes play a critical role in chronic rejection of transplanted hearts, or cardiac allograft vasculopathy (CAV). However, the molecular mediators of T lymphocyte recruitment in CAV are incompletely defined. We hypothesized that the chemokine, monokine induced by interferon-γ (MIG/CXCL9), which induces T lymphocyte migration in vitro, participates in T lymphocyte recruitment in CAV. In a previously characterized MHC II-mismatched murine model of CAV, intragraft MIG/CXCL9 gene transcript and protein levels increased on days 7, 14, and 24 days after transplantation, paralleling T lymphocyte recruitment and preceding intimal thickening. Antibody neutralization of MIG/CXCL9 significantly reduced CD4^{T lymphocyte infiltration and intimal thickening in this model. MIG/CXCL9 was produced by graft-infiltrating MOMA-2+ macrophages in early and late stages of CAV. And, although T lymphocytes did not produce MIG/CXCL9, recipient CD4}^{T lymphocytes were required for sustained intragraft MIG/CXCL9 production and CAV development. These findings demonstrate that 1) MIG/CXCL9 plays an important role in CD4}^{T lymphocyte recruitment and development of CAV, 2) MOMA-2+ macrophages are the predominant recipient-derived source of MIG/CXCL9, and 3) recipient CD4 lymphocytes are necessary for sustained MIG/CXCL9 production and CAV development in this model. Neutralization of the chemokine MIG/CXCL9 may have therapeutic potential for the treatment of chronic rejection after heart transplantation.}

Abstract

Chronic rejection of transplanted organs remains the major barrier to the long-term success of clinical transplantation. In transplanted hearts, the primary manifestation of chronic rejection is cardiac allograft vasculopathy (CAV). CAV is characterized by diffuse, concentric intimal thickening of the donor heart arteries and veins, and is currently the leading cause of late allograft failure. There has been limited success with pharmacological therapy or revascularization procedures in this disorder.¹

Both alloantigen-dependent and -independent factors have been shown to contribute to the development of CAV.² However, the host immune responses to the disparate alloantigens are the dominant factor in the development of CAV. Both CD4 and CD8 lymphocytes participate in the initiation and progression of lesion development.^3,4 Despite their well-known causal role in CAV, the molecular mechanisms that mediate T lymphocyte recruitment into the graft are not fully defined.

Chemokines, a subfamily of cytokines, induce the directional migration of T lymphocytes and other mononuclear cells in vitro and in vivo.⁵ Reports from other laboratories and our group have demonstrated up-regulation of various chemokines correlating with T lymphocyte recruitment, during acute and chronic rejection of allografts.^6,7 The interferon (IFN)-γ-inducible CXC chemokine, monokine induced by IFN-γ (MIG/CXCL9), is a potent chemotactic factor for T lymphocytes, and has been shown to contribute to a variety of inflammatory disorders.^8-10 The importance of MIG/CXCL9 in acute rejection of allografts has been documented.^11,12 Miura and colleagues¹² demonstrated that MIG/CXCL9 is a dominant factor in recruitment of T lymphocytes in acute rejection of MHC-mismatched cardiac allografts. In contrast, the role of MIG/CXCL9 in CAV remains unknown.

In a previously characterized MHC II-mismatched murine model of CAV, we have observed a temporal correlation between intragraft IFN-γ level and mononuclear cell recruitment. We hypothesized that intragraft IFN-γ induces up-regulation of MIG/CXCL9, which in turn may mediate the T lymphocyte recruitment in this model of CAV. First, we sought to define the time course of intragraft MIG/CXCL9 production in relation to T lymphocyte recruitment and CAV development. Second, with a neutralizing antibody to MIG/CXCL9, we aimed to determine the functional role of MIG/CXCL9 on T lymphocyte recruitment and CAV development in this MHC II-mismatched model of CAV. We also sought to determine which graft-infiltrating cells produced MIG/CXCL9 in this model. And lastly, we investigated the relationship between recipient CD4 lymphocytes and intragraft MIG/CXCL9 level.

P < .05 when compared to control antibody.

Anti-MIG/CXCL9 demonstrated specific neutralization of murine MIG/CXCL9 and inhibition of chemotaxis.

Footnotes

Address reprint requests to Abbas Ardehali, M.D., Division of Cardiothoracic Surgery, 62-246 CHS, UCLA Medical Center, 10833 Le Conte Ave., Los Angeles, CA 90095. E-mail: .ude.alcu.tendem@ilahedraa

Supported by funds from the American Association for Thoracic Surgery (Second Alfred Blalock Award to A. A.), the American Heart Association (0130105N to A. A.), the Piansky Family Trust (to M. C. F.), and the National Institutes of Health (PO1 HL30568 to J. A. B., T32 AI07126-23 to J. J. Y., and P01 HL67665 to R. M. S.).

Footnotes

References

1. Weis M, Von Scheidt W: Cardiac allograft vasculopathy. Circulation 1997, 96:2069-2077 [[PubMed]
2. Tullius SG, Tilney NL: Both alloantigen-dependent and independent factors influence chronic allograft rejection. Transplantation 1995, 59:313-318 [[PubMed]
3. Shi C, Lee WS, He Q, Zhang D, Fletcher DL, Newell JB, Haber E: Immunologic basis of transplant-associated arteriosclerosis. Proc Natl Acad Sci USA 1996, 93:4051-4056
4. Fischbein MP, Yun J, Laks H, Irie Y, Fishbein MC, Espejo M, Bonavida B, Ardehali A: CD8+ lymphocytes augment chronic rejection in a MHC class II mismatched model. Transplantation 2001, 71:1146-1153 [[PubMed]
5. Gerard C, Rollins B: Chemokines and disease. Nat Immunol 2001, 2:108-115 [[PubMed]
6. Kondo TA, Novick C, Toma H, Fairchild RL: Induction of chemokine gene expression during allogeneic skin graft rejection. Transplantation 1996, 61:1750-1757 [[PubMed]
7. Yun J, Fischbein MF, Laks H, Fishbein MC, Espejo M, Ebrahimi K, Irie Y, Berliner JA, Ardehali A: Early and late chemokine production correlates with cellular recruitment in cardiac allograft vasculopathy. Transplantation 2000, 69:2515-2524 [[PubMed]
8. Bradley LM, Asensio VC, Schoitz LK, Harbertson J, Krahl T, Patstone G, Woolf N, Campbell IL, Savertnick N: Islet-specific Th1 but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes. J Immunol 1999, 162:2511-2520 [[PubMed]
9. Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH: Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 1999, 163:6236-6243 [[PubMed]
10. Liu MT, Armstrong D, Hamilton TA, Lane TE: Expression of Mig (monokine induced by interferon-γ) is important in T lymphocyte recruitment and host defense following viral infection of the central nervous system. J Immunol 2001, 166:1790-1795 [[PubMed]
11. Koga S, Auerbach MB, Engeman TM, Novick AC, Toma H, Fairchild RL: T cell infiltration into class II MHC-disparate allografts and acute rejection is dependent on the IFN-gamma-induced chemokine Mig. J Immunol 1999, 163:4878-4885 [[PubMed]
12. Miura M, Morita K, Kobayashi H, Hamilton TA, Burdick MD, Strieter RM, Fairchild RL: Monokine induced by IFN-gamma is a dominant factor directing T cells to murine cardiac allografts during acute rejection. J Immunol 2001, 167:3494-3504 [[PubMed]
13. Corry R, Winn H, Russell P: Primarily vascularized allografts of hearts in miceThe role of H-2D, H-2K, and non-H-2 antigens in rejection. Transplantation 1973, 16:343-350 [[PubMed][Google Scholar]
14. Belperio JA, Keane MP, Burdick MD, Lynch JP, III, Xue YY, Berlin A, Ross DJ, Kunkel SL, Charo IF, Strieter RM: Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome in lung transplant recipients. J Clin Invest 2001, 108:547-554
15. Yun J, Fischbein MP, Laks H, Irie Y, Espejo M, Fishbein MC, Berliner J, Ardehali A: RANTES production during development of cardiac allograft vasculopathy. Transplantation 2001, 71:1649-1656 [[PubMed]
16. Fischbein MP, Ardehali A, Yun J, Schoenberger S, Laks H, Irie Y, Dempsey P, Cheng G, Fishbein MC, Bonavida B: CD40 signaling replaces CD4+ lymphocytes and its blocking prevents chronic rejection of heart transplants. J Immunol 2000, 165:7316-7322 [[PubMed]
17. Ring GH, Saleem S, Dai Z, Hassan AT, Zonieczny BT, Baddoura FK, Lakkis FG: Interferon-gamma is necessary for initiating the acute rejection of major histocompatibility complex class II-disparate skin allografts. Transplantation 1999, 67:1362-1365 [[PubMed]
18. Fischbein MP, Yun J, Laks H, Irie Y, Fishbein MC, Bonavida B, Ardehali A: Role of CD8+ lymphocytes in chronic rejection of transplanted hearts. J Thorac Cardiovasc Surgery 2002, 123:803-809 [[PubMed]
19. Agostini C, Facco M, Siviero M, Carollo D, Galvan S, Cattelan A, Zambello R, Trentin L, Semenzato G: CXC chemokines IP-10 and Mig expression directs migration of pulmonary CD8+/CXCR3+ T cells in the lungs of patients with HIV infection and T-cell alveolitis. Am J Respir Crit Care Med 2000, 162:1466-1473 [[PubMed]
20. Hancock WW, Lu B, Gao W, Csizmadia V, Faia K, King JA, Smiley ST, Ling M, Gerard NP, Gerard C: Requirement of the chemokine receptor CXCR3 for acute allograft rejection. J Exp Med 2000, 192:1515-1520
21. Kunz MA, Toksoy M, Goebeler M, Engelhardt E, Brocker E, Gillitzer R: Strong expression of the lymphoattractant C-X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma. J Pathol 1999, 189:552-558 [[PubMed]
22. Kapoor A, Morita K, Engeman TM, Koga S, Vapnek EM, Hobart MG, Fairchild RL: Early expression of interferon-γ inducible protein 10 and monokine induced by interferon-γ in cardiac allografts is mediated by CD8+ T cells. Transplantation 2000, 69:1147-1155 [[PubMed]