Transient Chemokine Receptor Blockade does not Prevent, but may Accelerate Type 1 Diabetes in Prediabetic NOD Mice

Abstract

The influx of autoreactive lymphocytes into the site of an autoimmune inflammation is mediated by certain chemokines. Autoimmune insulitis in type 1 diabetes is viewed as the result of destructive Th-1-cells and their corresponding antigen-presenting cells infiltrating the pancreatic islets. Blocking the chemokine receptors that mediate a Th-1-reaction has been shown to reduce autoimmunity in other experimental autoimmune disorders. We used the NOD mouse model to investigate the potency of anti-CCR2 and anti-CCR5 antibodies to inhibit the influx of Th-1-cells into the pancreatic islets, thus preventing diabetes onset. Eleven-week-old female NOD mice were treated with 500 µg of a monoclonal anti-CCR5 or anti-CCR2 or an isotype control antibody every third day over two weeks. We did not observe any preventive effect in either treatment group, but accelerated diabetes onset in the anti-CCR5 treated group. The number of autoantigen-specific Th-1-cells detected in the two treated groups was not reduced, but increased in the anti-CCR5 group. Redundancy within the chemokine system may account for this lack of prevention, or the intervention may have come too late in the disease process. Furthermore, blocking Th-1 chemokine receptors in the late autoimmune process may also inhibit regulatory T-cells, thus accelerating rather than preventing the disease.

Key words

Autoimmune insulitis - regulatory T-cells - Th-1 cells - CCR2 - CCR5 - redundancy

References

• 1 Diabetes Prevention Trial-Type 1 Diabetes Study Group . Effects of insulin in relatives of patients with type 1 diabetes mellitus.  N Engl J Med. 2001;  346 1685-1691
• 2 Luster A D. Chemokines - chemotactic cytokines that mediate inflammation.  N Engl J Med. 1998;  338 436-445
• 3 Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity.  Immunity. 2000;  12 121-127
• 4 Bradley L M, Asensio V C, Schioetz L K, Harbertson J, Krahl T, Patstone G, Woolf N, Campbell I L, Sarvetnick N. Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes.  J Immunol. 1999;  162 2511-2520
• 5 Cameron M J, Arreaza G A, Grattan M, Meagher C, Sharif S, Burdick M D, Strieter R M, Cook D N, Delovitch T L. Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes.  J Immunol. 2000;  165 1102-1110
• 6 Gazda L S, Charlton B, Lafferty K J. Diabetes results from a late change in the autoimmune response of NOD mice.  J Autoimmun. 1997;  10 261-270
• 7 Sallusto F, Lanzavecchia A, Mackay C R. Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses.  Immunol Today. 1998;  19 568-574
• 8 Xie J H, Nomura N, Lu M, Chen S L, Koch G E, Weng Y, Rosa R, Di Salvo J, Mudgett J, Peterson L B, Wicker L S, DeMartino J A. Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitment of T helper 1 cells into sites of inflammation.  J Leukoc Biol. 2003;  73 771-780
• 9 Yang Y F, Mukai T, Gao P, Yamaguchi N, Ono S, Iwaki H, Obika S, Imanishi T, Tsujimura T, Hamaoka T, Fujiwara H. A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses.  Eur J Immunol. 2002;  32 2124-2132
• 10 Traynor T R, Herring A C, Dorf M E, Kuziel W A, Toews G B, Huffnagle G B. Differential roles of CC chemokine ligand 2/monocyte chemotactic protein-1 and CCR2 in the development of T1 immunity.  J Immunol. 2002;  168 4659-4666
• 11 Mack M, Brühl H, Gruber R, Jaeger C, Cihak J, Eiter V, Plachy J, Stangassinger M, Uhlig K, Schattenkirchner M, Schlondorff D. Predominance of mononuclear cells expressing the chemokine receptor CCR5 in synovial effusions of patients with different forms of arthritis.  Arthritis Rheum. 1999;  42 981-988
• 12 Mack M, Cihak J, Simonis C, Luckow B, Proudfoot A E, Plachy J, Bruhl H, Frink M, Anders H J, Vielhauer V, Pfirstinger J, Stangassinger M, Schlondorff D. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice.  J Immunol. 2001;  166 4697-4704
• 13 Weaver D J, Liu B, Tisch R. Plasmid DNAs encoding insulin and glutamic acid decarboxylase 65 have distinct effects on the progression of autoimmune diabetes in nonobese diabetic mice.  J Immunol. 2001;  167 586-592
• 14 Anderson B, Park B J, Verdaguer J, Amrani A, Santamaria P. Prevalent CD8⁺ T cell response against one peptide/MHC complex in autoimmune diabetes.  Proc Natl Acad Sci. 1999;  96 9311-9316
• 15 Carvalho-Pinto C, Garcia M I, Gomez L, Ballesteros A, Zaballos A, Flores J M, Mellado M, Rodriguez-Frade J M, Balomenos D, Martinez-A C. Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non-obese diabetic mice.  Eur J Immunol. 2004;  34 548-557
• 16 Buhler M M, Craig M, Donaghue K C, Badhwar P, Willis J, Manolios N, Tait B D, Silink M, Bennetts B H, Stewart G J. CCR5 genotyping in an Australian and New Zealand type 1 diabetes cohort.  Autoimmunity. 2002;  35 457-461
• 17 Lohmann T, Laue S, Nietzschmann U, Kapellen T M, Lehmann I, Schroeder S, Paschke R, Kiess W. Reduced expression of Th1-associated chemokine receptors on peripheral blood lymphocytes at diagnosis of type 1 diabetes.  Diabetes. 2002;  51 2474-2480
• 18 Balashov K E, Rottman J B, Weiner H L, Hancock W W. CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions.  Proc Natl Acad Sci .. 1999;  96 6873-6878
• 19 Gomez-Reino J J, Pablos J L, Carreira P E, Santiago B, Serrano L, Vicario J L, Balsa A, Figueroa M, de Juan M D. Association of rheumatoid arthritis with a functional chemokine receptor, CCR5.  Arthritis Rheum. 1999;  42 989-992
• 20 Abdi R, Smith R N, Makhlouf L, Najafian N, Luster A D, Auchincloss H Jr, Sayegh M H. The role of CC chemokine receptor 5 (CCR5) in islet allograft rejection.  Diabetes. 2002;  51 2489-2495
• 21 Brühl H, Cihak J, Schneider M A, Plachy J, Rupp T, Wenzel I, Shakarami M, Milz S, Ellwart J W, Stangassinger M, Schlondorff D, Mack M. Dual role of CCR2 during initiation and progression of collagen-induced arthritis: evidence for regulatory activity of CCR2+ T cells.  J Immunol. 2004;  172 890-898
• 22 Welniak L A, Wang Z, Sun K, Kuziel W, Anver M R, Blazar B R, Murphy W J. An absence of CCR5 on donor cells results in acceleration of acute graft-vs-host disease.  Exp Hematol. 2004;  32 318-324