Cellular immunity

Several lines of evidence point to a central role for cell-mediated immunity in the pathogenesis of beta cell destruction that culminates in type 1 diabetes. Examples summarized in the article includes the transfer of diabetes by islet-reactive T cells in NOD mice, as well as with anecdotal evidence of inadvertent transfer of diabetes by bone marrow transplantation in humans. Historically, the identification of insulitis (i.e., an immune inflammation of the pancreatic islets) provided one of the first clues to an immune basis to type 1 diabetes. The nature of this islet infiltrate has been extensively characterized in both human and animals. Recurrence of such infiltrates has also been observed in association with loss of graft function in islet and pancreatic transplants. Finally, many studies have demonstrated that immune intervention directed against effector T cells can prevent diabetes in the NOD mouse.

Introduction

Type 1 diabetes mellitus is a chronic immune-mediated disease resulting from selective destruction of insulin producing beta-cells. Studies of the pancreas of persons with insulin requiring diabetes performed in the 1960s provided the first clear proof of an immune-mediated attack upon beta cells. Later studies identifying antibodies against these cells added to the notion that the disease was autoimmune in its nature. These antibodies appear many years before clinical onset of diabetes and form the basis for the prediction and classification of type 1 diabetes. Despite their importance in these roles, antibodies are generally considered an epiphenomenon of the immune process – markers rather than effectors of the immune attack. Histological evaluation of pancreas from patients with type 1 diabetes patients reveals insulitis - immune cell infiltrates around and in the islets – and cellular immune reactivity is considered to be the direct cause of beta-cell destruction, mainly mediated by T-lymphocytes / T-cells. The mechanisms leading to islet-directed immune reactivity are not yet understood, but partial breakdown of what is commonly called central or peripheral tolerance, a defect of T regulatory cells and a possible role for innate immunity are currently under consideration. Many forms of immune intervention have been developed and tested in the quest to halt immune mediated beta-cell destruction. [1]

T reg; T regulatory cells  EC; endothelial cells EP; epithelial cells DC; dendritic cells
T reg; T regulatory cells EC; endothelial cells EP; epithelial cells DC; dendritic cells

Cellular immune reactivity in animal models of type 1 diabetes

Diabetes transfer with T cells in NOD mice

First evidence of a pathogenic role of T cells in immune-mediated beta-cell destruction came from animal experiments with NOD (non-obese diabetic) mice that are used as a model for type 1 diabetes. Whereas islet directed antibodies or B-lymphocytes could not transfer diabetes into healthy animals, diabetes could be transferred with islet reactive T cells that were isolated from the islet infiltrate or spleen from diabetic donor NOD mice [2].

Islet antigen specific T cells in NOD mice

On the search for antigen-reactivity of disease transferring T cells, several different antigens including islet antigens insulin, GAD65, IA2, hsp60, ZnT8, Chromogranin A and their peptides have been identified [3]. When these T cells were characterized further, they were of CD4 (T helper) or CD8 (T cytotoxic) phenotype and often secreted pro-inflammatory Th1 cytokines such as Interferon-gamma. Islet antigen reactive T cells of Th2 phenotype, secreting Interleukin-4 and Interleukin-10 have been considered benign or non-destructive. Regulatory T cells are thought to play crucial role in controling the evolvement of ß-cell destructive autoimmunity.[4]

Cellular immune reactivity in human subjects with type 1 diabetes

Islet antigen reactive T cells in human subjects with type 1 diabetes

Similar to mice, islet reactive T cells also exist in human subjects with type 1 diabetes [5]. Studies identified insulin, GAD65, IA2, hsp60, ZnT8, Chromogranin A and their peptides as target antigens of T cells in type 1 diabetes patients. As observed from animal models, they were of CD4 or CD8 phenotype and most often secreted proinflammatory cytokines thereby showing a close analogy to the animal experiments. An association of T cell reactivity with beta-cell function has been described [6]. Islet antigen specific T cell reactivity was also observed in a patient who had a functional defect of B-lymphocytes [7].

Type 1 diabetes transfer in human subjects

Although islet reactive T cells had been detected in human subjects with type 1 diabetes, observations that bone marrow transfer leads to type 1 diabetes to non-diabetic subjects confirmed the important pathogenic role of cellular immune reactivity in type 1 diabetes [8].

Recurrence of immune-infiltrate in islet and pancreatic transplants

Further evidence that cellular reactivity is causal for islet destruction comes from observations in patients with type 1 diabetes who received islet transplants or pancreatic transplants reactivated autoimmunity[9]. Interestingly, T cell reactivity against islet antigens as well as T cell reactivity against allo-antigens as frequently observed in transplant immunology were associated with the non-functioning of the graft [10].

Islet-reactive T cells in human pancreatic islets

Reports from autopsies of newly diagnosed type 1 diabetes patients have shown, that islet infiltrating T cells are antigen-specific, of CD4 or CD8 phenotype thereby strengthening the pathogenic role of these T cells [11].

Detection of T cells

Whereas the detection and measurement of islet antibodies has been standardized and is available as commercial kits, T cell reactivity is more difficult to detect as the number of antigen-reactive T cells in the peripheral blood is low and the magnitude of responses is on the low side[12]. Several methods have been applied to measure and characterize T cell reactivity. T cells can be characterized ex vivo by proliferation experiments, by cell surface analysis using flow cytometry and tetramer technology, by ELISPOT that is enumeration of cytokine secreting T cells that are antigen-stimulated, by Qdot analysis. Upon several days of cell culture T cell lines and T cell clones have been obtained and used for in depth characterization. Currently, efforts to standardize T cell assays are under development.[12]

Innate immunity in type 1 diabetes

Although T cells are considered main pathogenic players, the role of innate immune reactivity for beta-cell destruction has been established as the cross-talk of different immune cells plays an important role for immune reactivity. Analyses of the interactions between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have highlighted how these different cell populations can influence the onset of autoimmunity. There is evidence that infection can have either a potentiating or inhibitory role in the development of type 1 diabetes [13]. Further, Toll like receptors on macrophages have been shown to play a role in islet directed immunity [14].

Cytokines and chemokines in type 1 diabetes

Cytokines such as IL-1, TNF-alpha and Interferon-gamma are secreted by immune cells and can directly harm beta-cells [15]. Furthermore, cytokines and chemokines modulate, activate, regulate and attract other immune cells and thereby play a crucial role in cellular immune reactivity. So far, complex up- and downregulation of systemic cytokines and chemokines in patients with type 1 diabetes and subjects at increased diabetes risk [16] [17] and in relation to ß-cell function and clinical remission in type 1 diabetes patients have been described [18].

Targeting celluar immune reactivity in immune intervention trials

As T cells have been identified as important pathogenic player in islet destruction, several attempts have been undertaken to alter or deplete T cell reactivity in vivo to stop islet destruction. However, also other immune directed interventions are currently evaluated [19].

Antigen-directed approaches

Antigen directed therapy with GAD65, insulin, proinsulin, hsp60 and other islet antigens have successfully shown to halt islet destruction or even cure immune-mediated diabetes in mouse models by modulation T cell reactivity[20]. However, in human subjects with type 1 diabetes only partial success has been achieved to maintain endogenous insulin secretory capacity and several phase I, II and III studies are under way [21].

Targeting of T cells

T cell directed treatment with anti-CD3 or abatacept leads to a modulation of T cells and has been shown to successfully prevent or ameliorate islet destruction in animal models. However, data in humans are conflicting and only partial success has been achieved[22]

Targeting of B-lymphocytes

B-lymphocyte directed treatment with rituximab (anti-CD20) has been tested in humans in phase II trials and is currently under further evaluation [23]

Anti-inflammatory approaches

Several approaches to intervene in experimental diabetes or type 1 diabetes are currently under evaluation. Studies in mouse and men are currently performed with atorvastatin [24], etanercept (anti-TNFa) [25], Anakinra (IL1 receptor antagonist)[26] , and ingested interferon [27]

Cellular based intervention

Several attempts are currently employed in human subjects, e.g. autologous non-myeloablative hematopoetic stem cell transplantation [28], autologous bone marrow transplantation [29], cord blood transfusion [30], autologous dendritic cell transfer[31] etc.

References

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  2. ^ Haskins K. CD4 T cells and their antigens in the pathogenesis of autoimmune diabetes. Curr Opin Immunol. 2011 Dec;23(6):739-45.

  3. ^ Babad J, et al. T-cell autoantigens in the non-obese diabetic mouse model of autoimmune diabetes. Immunology 2010;131(4):459-65

  4. ^ Bluestone JA, Tang Q, Sedwick CE. T regulatory cells in autoimmune past challenges, future prospects. J Clin Immunol 2008 Nov;28(6):677-84.

  5. ^ Roep BO, Peakman M. Diabetogenic T lymphocytes in human Type 1 diabetes. Curr Opin Immunol. 2011 Dec;23(6):746-53

  6. ^ Pfleger C, et al. Association of T-cell reactivity with beta-cell function in recent onset type 1 diabetes patients. J Autoimmun 2010 Mar;34(2):127-35

  7. ^ Martin S, et al. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N Engl J Med 2001 Oct 4;345(14):1036-40

  8. ^ Lampeter EF, McCann SR, Kolb H. Transfer of diabetes type 1 by bone-marrow transplantation. Lancet. 1998 Feb 21;351(9102):568-9.

  9. ^ Burke et al. Recurrence of autoimmunity following pancreas transplantation. Curr Diab Rep 2011 Oct;11(5):413-419

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  11. ^ Atkinson et al. The pancreas in human type 1 providing new answers to age-old questions. Curr Opin Endocrinol Diabetes Obes 2009 Aug;16(4):279-85.

  12. ^ Mannering SI et al. Current approaches to measuring human islet-antigen specific T cell function in type 1 diabetes. Immunology of Diabetes Society T-Cell Workshop Committee. Clin Exp Immunol. 2010 Nov;162(2):197-209.

  13. ^ Lehuen A, et al. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 2010 Jul;10(7):501-13

  14. ^ Grieco FA, et al. Innate immunity and the pathogenesis of type 1 diabetes. Semin Immunopathol 2011 Jan;33(1):57-66

  15. ^ Mandrup-Poulsen T et al. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol. 2010 Mar;6(3):158-66

  16. ^ Hanifi-Moghaddam P et al. An association of autoantibody status and serum cytokine levels in type 1 diabetes. Diabetes 2003 May;52(5):1137-42

  17. ^ Hanifi-Moghaddam P, et al. Altered chemokine levels in individuals at risk of Type 1 diabetes mellitus. Diabet Med 2006 Feb;23(2):156-63

  18. ^ Pfleger C, et al. Association of IL-1ra and adiponectin with C-peptide and remission in patients with type 1 diabetes. Diabetes 2008 Apr;57(4):929-37

  19. ^ Bluestone JA et al: Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010 Apr 29;464(7293):1293-300.

  20. ^ Bowman MA, et al. Prevention of diabetes in the NOD mouse: implications for therapeutic intervention in human disease. Immunol Today. 1994 Mar;15(3):115-20.

  21. ^ Ludvigsson NEJM 2008, Raz Lancet 2001, Throuwer Clin Exp Immunol 2009 Feb;155(2):156-65. Vehik Diabetes Care. 2011 Jul;34(7):1585-90. Näntö-Salonen K Lancet. 2008 Nov 15;372(9651):1746-55

  22. ^ Keymeulen, 2005, NEJM (Otelixizumab); Herold, 2005 Diabetes (Teplizumab) Abatacept (Orban T Lancet Lancet. 2011 Jul 30;378(9789):412-9

  23. ^ Pescovitz MD, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 2009 Nov 26;361(22):2143-52.

  24. ^ Martin et al. Residual beta cell function in newly diagnosed type 1 diabetes after treatment with atorvastatin: the Randomized DIATOR Trial. PLoS One. 2011 Mar 11;6(3):e17554

  25. ^ Mastrandrea L et al. Etanercept treatment in children with new-onset type 1 pilot randomized, placebo-controlled, double-blind study. Diabetes Care. 2009 Jul;32(7):1244-9

  26. ^ Pickersgill LM, Mandrup-Poulsen TR. The anti-interleukin-1 in type 1 diabetes action trial--background and rationale. Diabetes Metab Res Rev. 2009 May;25(4):321-4.

  27. ^ Rother KI et al. Effect of ingested interferon-alpha on beta-cell function in children with new-onset type 1 diabetes. Diabetes Care July;32(7): 1250-1255

  28. ^ Voltarelli JC et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA (2007),1568- 1576

  29. ^ Esmatjes E et al. Regeneration of insulin production by autologous bone marrow blood autotransplantation in patients with type 1 diabetes. Diabetologia. 2010 Apr;53(4):786-9. Epub 2010 Jan 26

  30. ^ Haller MJ et al. Autologous umbilical cord blood transfusion in young children with type 1 diabetes fails to preserve C-peptide. Diabetes Care. 2011 Dec;34(12):2567-9. Epub 2011 Oct 19.

  31. ^ Giannoukakis N et al. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care 2011. Sep;34(9):2026-32. Epub 2011 Jun 16.

Comments

  1. Anna Harding
    Anna Harding added a suggestion on 1 September 2014 at 12:58PM
    Thank you for your comment, this reference has now been updated.
  2. no profile image
    Ralph Ellison added a suggestion on 25 August 2014 at 10:14AM
    Great overview. Would be nice if proofread though - the references look like a PhD draft, e.g.
    "19. Bluestone JA et al: Genetics, pathogenesis and clinical interventions in type 1 diabetes."
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