Targeting Memory T Cells in Type 1 Diabetes

Current Diabetes Reports

Volumn 15, Issue 11, 2015, Pages

  Ehlers, Mario R ^a   Rigby, Mark R ^b  

^a Immune Tolerance Network   (United States)

^b Janssen Pharmaceuticals R D LLC   (United States)

Author keywords

Alefacept; Autoimmunity; CD2; CD3; Central memory T cells; Costimulation blockade; Effector memory T cells; Homeostatic cytokines

Indexed keywords

ABATACEPT; ALEFACEPT; AMG 714; ANTIBODY; CD2 ANTIBODY; CD3 ANTIBODY; CD48 ANTIBODY; CYTOKINE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 ANTIBODY; DALAZATIDE; GRANULOCYTE COLONY STIMULATING FACTOR; IMMUNOMODULATING AGENT; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 7 RECEPTOR ALPHA ANTIBODY; MONOCLONAL ANTIBODY; OTELIXIZUMAB; PLACEBO; PREDNISONE; RECEPTOR ANTIBODY; TEPLIZUMAB; THYMOCYTE ANTIBODY; UNCLASSIFIED DRUG;

ALLOTRANSPLANTATION; AUTOIMMUNE DISEASE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DESTRUCTION; CELL EXPANSION; CHRONIC DISEASE; DISEASE COURSE; DOWN REGULATION; DRUG TARGETING; HUMAN; IMMUNOSTIMULATION; INSULIN DEPENDENT DIABETES MELLITUS; MEMORY T LYMPHOCYTE; NONHUMAN; PANCREAS ISLET BETA CELL; PANCREAS ISLET CELL FUNCTION; PANCREAS ISLET TRANSPLANTATION; PSORIASIS; REGULATORY T LYMPHOCYTE; REVIEW; RHEUMATOID ARTHRITIS; STEM CELL TRANSPLANTATION; T CELL DEPLETION; T LYMPHOCYTE ACTIVATION; ANIMAL; HOMEOSTASIS; IMMUNOLOGICAL MEMORY; IMMUNOLOGY; SIGNAL TRANSDUCTION; T LYMPHOCYTE;

ANIMALS; CYTOKINES; DIABETES MELLITUS, TYPE 1; HOMEOSTASIS; HUMANS; IMMUNOLOGIC MEMORY; SIGNAL TRANSDUCTION; T-LYMPHOCYTES;

EID: 84941910042     PISSN: 15344827     EISSN: 15390829     Source Type: Journal    
DOI: 10.1007/s11892-015-0659-5     Document Type: Review

References (87)

1. Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464:1293–300.
2. Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371:1972–82. An important study showing that even with good glycemic control, T1D results in substantial excess mortality.
3. Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care. 2003;26:832–6.
4. Todd JA. Etiology of type 1 diabetes. Immunity. 2010;32:457–67.
5. Wang P, Fiaschi-Taesch NM, Vasavada RC, et al. Diabetes mellitus—advances and challenges in human β-cell proliferation. Nat Rev Endocrinol. 2015;11:201–12.
6. Coppieters KT, Wiberg A, Tracy AM, et al. Immunology in the clinic review series: focus on type 1 diabetes and viruses: the role of viruses in type 1 diabetes: a difficult dilemma. Clin Exp Immunol. 2012;168:5–11.
7. Schneider A, Rieck M, Sanda S, et al. The effector T cells of diabetic subjects aqre resistant to regulation via CD4+FOXP3+ regulatory T cells. J Immunol. 2008;181:7350–5.
8. Danke NA, Yang J, Greenbaum C, et al. Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects. J Autoimmun. 2005;25:303–11.
9. Monti P, Scirpoli M, Rigamonti A, et al. Evidence for in vivo primed and expanded autoreactive T cells as a specific feature of patients with type 1 diabetes. J Immunol. 2007;179:5785–92.
10. Oling V, Reijonen H, Simell O, et al. Autoantigen-specific memory CD4+ T cells are prevalent early in progression to type 1 diabetes. Cell Immunol. 2012;273:133–9. One of several studies showing that islet-reactive CD4+T cells are found in the peripheral blood of healthy subjects but that these cells tend to have a naïve phenotype versus the memory phenotype found in subjects with T1D autoimmunity.
11. Skowera A, Ladell K, McLaren JE, et al. β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure. Diabetes. 2015;64:916–25. An important study showing that beta cell-specific CD8+T cells in patients with T1D tend to have a stem memory phenotype and are characterized by a highly skewed oligoclonal T cell receptor repertoire.
12. Sutherland DE, Sibley R, Xu XZ, et al. Twin-to-twin pancreas transplantation: reversal and reenactment of the pathogenesis of type I diabetes. Trans Assoc Am Physicians. 1984;97:80–7.
13. Sibley RK, Sutherland DER, Goetz F, et al. Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest. 1985;53:132–44.
14. Sutherland DER, Goetz FC, Sibley RK. Recurrence of diabetes in pancreas transplants. Diabetes. 1989;38 Suppl 1:85–7.
15. Tyden G, Reinholt FP, Sundkvist G, et al. Recurrence of autoimmune diabetes mellitus in recipients of cadaveric pancreatic grafts. New Engl J Med. 1996;335:860–2.
16. Roep BO, Stobbe I, Duinkerken G, et al. Auto- and alloimmune reactivity to human islet allografts trasnplanted into type 1 diabetic patients. Diabetes. 1999;48:484–90.
17. Pinkse GGM, Tysma OHM, Bergen CAM, et al. Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes. Proc Natl Acad Sci U S A. 2005;102:18425–30.
18. Laughlin E, Burke G, Pugliese A, et al. Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation. Clin Immunol. 2008;128:23–30.
19. Monti P, Scirpoli M, Maffi P, et al. Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest. 2008;118:1806–14.
20. Vendrame F, Pileggi A, Laughlin E, et al. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes. 2010;59:947–57.
21. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63.
22. Chang JT, Wherry EJ, Goldrath AW. Molecular regulation of effector and memory T cell differentiation. Nat Immunol. 2014;15:1104–15. An excellent recent review of our understanding of memory T cell differentiation and function.
23. Devarajan P, Chen Z. Autoimmune effector memory T cells: the bad and the good. Immunol Res. 2013;57:12–22. A useful review of the memory T cell compartment in autoimmunity, with an emphasis on Tem cells.
24. Chee J, Ko HJ, Skowera A, et al. Effector-memory T cells develop in islets and report islet pathology in type 1 diabetes. J Immunol. 2014;192:572–80. An important study in the NOD model demonstrating that acquisition of the effector-memory phenotype by islet-specific CD8+T cells occurs in infiltrated islets, followed by emigration to peripheral lymphoid tissue.
25. Orban T, Beam CA, Xu P, et al. Reduction in CD4 central memory T-cell subset in costimulation modulator abatacept-treated patients with recent-onset type 1 diabetes is associated with slower C-peptide decline. Diabetes. 2014;63:3449–57. The first demonstration that CD4+Tcm cells are down-modulated by costimulation blockade (abatacept) and that this correlates with C-peptide preservation.
26. Surh CD, Sprent J. Homeostasis of naïve and memory T cells. Immunity. 2008;29:848–62.
27. Calzascia T, Pellegrini M, Lin A, et al. CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Proc Natl Acad Sci U S A. 2008;105:2999–3004.
28. Penaranda C, Kuswanto W, Hofmann J, et al. IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells. Proc Natl Acad Sci U S A. 2012;109:12668–73. Together with the study by Lee et al. (ref. 29), the first demonstration that IL-7 receptor blockade robustly reverses diabetes in NOD mice by inhibiting Tem cells and upregulating PD-1 expression.
29. Lee LF, Logriono K, Tu GH, et al. Anti-IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function. Proc Natl Acad Sci U S A. 2012;109:12674–9. See comment relating to ref. 28.
30. Murakami N, Riella LV. Co-inhibitory pathways and their importance in immune regulation. Transplantation. 2014;98:3–14. An excellent recent review of co-inhibitory and co-stimulatory pathways in immune regulation.
31. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–42.
32. Pauken KE, Jenkins MK, Azuma M, Fife BT. PD-1, but not PD-L1, expressed by islet-reactive CD4+ T cells suppresses infiltration of the pancreas during type 1 diabetes. Diabetes. 2013;62:2859–69. One of several studies indicating that the PD-1 pathway may be important in maintaining peripheral tolerance in the NOD model of diabetes autoimmunity.
33. Ansari MJ, Salama AD, Chitnis T, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med. 2003;198:63–9.
34. Fife BT, Guleria I, Gubbels Bupp M, et al. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med. 2006;203:2737–47.
35. Li R, Lee J, Kim MS, et al. PD-L1-driven tolerance protects neurogenin3-induced islet neogenesis to reverse established type 1 diabetes in NOD mice. Diabetes. 2015;64:529–40.
36. Waldmann TA. Targeting the interleukin-15 system in rheumatoid arthritis. Arthritis Rheum. 2005;52:2585–8.
37. Baslund B, Tvede N, Danneskiold-Samsoe B, et al. Targeting interleukin-15 in patients with rheumatoid arthritis. A proof-of-concept study. Arthritis Rheum. 2005;52:2686–92.
38. Finch DK, Midha A, Buchanan CL, et al. Identification of a potent anti-IL-15 antibody with opposing mechanisms of action in vitro and in vivo. Br J Pharmacol. 2011;162:480–90.
39. Krueger GG. Selective targeting of T cell subsets: focus on alefacept—a remittive therapy for psoriasis. Expert Opin Biol Ther. 2002;2:431–41.
40. Chamian F, Lin SL, Lee E, et al. Alefacept (anti-CD2) causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis. J Transl Med. 2007;5:27.
41. Haider AS, Lowes MA, Gardner H, et al. Novel insight into the agonistic mechanism of alefacept in vivo: differentially expressed genes may serve as biomarkers of response in psoriasis patients. J Immunol. 2007;178:7442–9.
42. Punch JD, Lin J, Bluestone J, et al. CD2 and CD3 receptor-mediated tolerance: constraints on T cell activation. Transplantation. 1999;67:741–8.
43. Chamian F, Lowes MA, Lin SL, et al. Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci U S A. 2005;102:2075–80.
44. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med. 2001;345:248–55.
45. Rigby MR, DiMeglio LA, Rendell MS, et al. Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol. 2013;1:284–94. The first demonstration in the clinic that targeting the CD2 pathway leads to robust depletion of Tem cells, an increase in the Treg/Tem ratio, and preservation of C-peptide in new-onset T1D.
46. Barlow AK, Like AA. Anti-CD2 monoclonal antibodies prevent spontaneous and adoptive transfer of diabetes in the BB/Wor rat. Am J Pathol. 1992;141:1043–51.
47. Bai Y, Fu S, Honig S, et al. CD2 is a dominant target for allogeneic responses. Am J Transplant. 2002;2:618–26.
48. Chavin KD, Qin L, Lin J, et al. Combined anti-CD2 and anti-CD3 receptor monoclonal antibodies induce donor-specific tolerance in a cardiac transplant model. J Immunol. 1993;151:7249–59.
49. Chavin KD, Qin L, Lin J, et al. Combination anti-CD2 and anti-CD3 monoclonal antibodies induce tolerance while altering interleukin-2, interleukin-4, tumor necrosis factor, and transforming growth factor-beta production. Ann Surg. 1993;218:492–501.
50. Chavin KD, Qin L, Lin J, et al. Anti-CD2 and anti-CD3 monoclonal antibodies synergize to prolong allograft survival with decreased side effects. Transplantation. 1993;55:901–8.
51. Chavin KD, Qin L, Lin J, et al. Anti-CD2 monoclonal antibodies synergize with anti-CD3 to prolong allograft survival and decrease cytokine production. Transplant Proc. 1993;25:823–4.
52. Kapur S, Khanna A, Sharma VK, et al. CD2 antigen targeting reduces intragraft expression of mRNA-encoding granzyme B and IL-10 and induces tolerance. Transplantation. 1996;62:249–55.
53. Kapur S, Sharma V, Khanna A, et al. Regulation of the anti-allograft response by targeting the CD2 antigen: a potential strategy for the creation of transplant tolerance. Surg Technol Int. 1996;5:233–40.
54. Krueger GG, Callis KP. Development and use of alefacept to treat psoriasis. J Am Acad Dermatol. 2003;49:S87–97.
55. Miller GT, Hochman PS, Meier W, et al. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med. 1993;178:211–22.
56. Kuhns MS, Davis MM, Garcia KC. Deconstructing the form and function of the TCR/CD3 complex. Immunity. 2006;24:133–9.
57. Chatenoud L, Thervet E, Primo J, et al. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci U S A. 1994;91:123–7.
58. Daifotis AG, Koenig S, Chatenoud L, et al. Anti-CD3 clinical trials in type 1 diabetes mellitus. Clin Immunol. 2013;149:268–78.
59. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692–8.
60. Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352:2598–608.
61. Herold KC, Gitelman SE, Masharani U, et al. A single course of anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005;54:1763–9.
62. Keymeulen B, Walter M, Mathieu C, et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia. 2010;53:614–23.
63. Sherry N, Hagopian W, Ludvigsson J, et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet. 2011;378:487–97.
64. Ambery P, Donner TW, Biswas N, et al. Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study. Diabet Med. 2014;31:399–402.
65. Aronson R, Gottlieb PA, Christiansen JS, et al. Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: results of the randomized phase III study in recent-onset human type 1 diabetes. Diabetes Care. 2014;37:2746–54.
66. Herold KC, Gitelman SE, Ehlers MR, et al. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes. 2013;62:3766–74. The first trial in new-onset T1D to clearly show that response to anti-CD3 therapy is heterogenous and that a responder group can be identified.
67. Penaranda C, Tang Q, Bluestone JA. Anti-CD3 therapy promotes tolerance by selectively depleting pathogenic cells while preserving regulatory T cells. J Immunol. 2011;187:2015–22.
68. Herold KC, Gitelman SE, Willi SM, et al. Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial. Diabetologia. 2013;56:391–400. The first demonstration that CD8+Tcm cells are modulated in patients with recent-onset T1D who are responders to anti-CD3 therapy.
69. Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol. 2001;19:225–52.
70. Linsley PS, Brady W, Urnes M, et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:561–9.
71. Ford ML, Adams AB, Pearson TC. Targeting co-stimulatory pathways: transplantation and autoimmunity. Nat Rev Nephrol. 2014;10:14–24.
72. Webster RM. The immune checkpoint inhibitors: where are we now? Nat Rev Drug Discov. 2014;13:883–4.
73. Linsley PS, Wallace PM, Johnson J, et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992;257:792–5.
74. Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008;224:166–82.
75. Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;378:412–9.
76. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11:7–13.
77. Eisenbarth GS, Srikanta S, Jackson R, et al. Anti-thymocyte globulin and prednisone immunotherapy of recent onset type 1 diabetes mellitus. Diabetes Res. 1985;2:271–6.
78. Gitelman SE, Gottlieb PA, Rigby MR, et al. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2013;1:306–16. The first adequately powered trial in new-onset T1D showing that treatment with antithymocyte globulin monotherapy does not deplete Tem cells and fails to preserve C-peptide.
79. Long SA, Rieck M, Sanda S, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes. 2012;61:2340–8.
80. Mordes JP, Bortell R, Doukas J, et al. The BB/Wor rat and the balance hypothesis of autoimmunity. Diabetes Metab Rev. 1996;12:103–9.
81. Smilek DE, Ehlers MR, Nepom GT. Restoring the balance: immunotherapeutic combinations for autoimmune disease. Dis Model Mech. 2014;7:503–13.
82. Haller MJ, Gitelman SE, Gottlieb PA, et al. Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes. J Clin Invest. 2015;125:448–55. An important pilot study demonstrating that combination therapy with low-dose antithymocyte globulin plus G-CSF in new-onset T1D appears to preserve C-peptide, possibly by inducing a favorable Treg/Teff ratio.
83. Gregori S, Mangia P, Bacchetta R, et al. An anti-CD45RO/RB monoclonal antibody modulates T cell responses via induction of apoptosis and generation of regulatory T cells. J Exp Med. 2005;201:1293–305.
84. Rus H, Pardo CA, Hu L, et al. The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. Proc Natl Acad Sci U S A. 2005;102:11094–9.
85. Beeton C, Wulff H, Standifer NE, et al. Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc Natl Acad Sci U S A. 2006;103:17414–9.
86. Kineta Announces Promising Top-line Clinical Results for Dalazatide; Target Implicated in Broad Array of Autoimmune Diseases. http://www.kinetabio.com/press_releases/PressRelease20150505_dalazatide.pdf: Kineta, Inc.; 2015.
87. Maecker HT, McCoy JP, Nussenblatt R. Standardizing immunophenotyping for the Human Immunology Project. Nat Rev Immunol. 2012;12:191–200.