(Journal Article): Imbalance in Th Cell Polarization and its Relevance in Type 1 Diabetes Mellitus
 
Sia C (Department of Immunology, United Biomedical Inc., 25 Davids Drive, Hauppage, New York 11788, USA, csia(at)unitedbiomedical.com )
 
IN: Rev Diabetic Stud 2005; 2(4):182-186
Impact Factor(s) of Rev Diabetic Stud: 0.125 (2006)

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ABSTRACT: Functional polarization of T helper (Th) subsets of lymphocytes has been implicated in promoting or conferring risk to Type 1 diabetes mellitus (T1DM) development in human and diabetic animal models. It is assumed that an immoderate preponderance of type 1 immunity establishes the prerequisite for this development. Over the past years, various immune-intervention strategies have been tested to protect diabetic animals from developing overt diabetes. These protocols implicate a protective mechanism that is attributed to a change in the set of autoreactive Th cells from their Th1 to the Th2 phenotype. The studies were aimed at improving the effectiveness of Th2 cells to secrete the principal cytokines, IL-4 and IL-10, in order to mediate protection from diabetes in NOD mice. In contrast, some immune-modulation protocols utilizing non-specific reagents report that diabetes protection is apparently attributed to preferential survival of both Th1 and Th2 cells, rather than via a shift from their Th1 to Th2 phenotypes. Even though we know that excessive immune responses against self antigens are also controlled and terminated by regulatory T cells, this article focuses on the polarization of Th effector cells and discusses the controversial findings regarding the Th1/Th2 hypothesis to draw a conclusion on its relevance in T1DM from the existing knowledge.

TYPE OF PUBLICATION: Review

REFERENCES:

1. Kim J, Woods A, Becker-Dunn E, Bottomly K. Distinct functional phenotypes of cloned 1a-restricted helper T cells. J Exp Med 1985. 162:188-201.
2. Mossman TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. 1. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986. 136:2348-2357.
3. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996. 17:138-146.
4. Romagnani S. Lymphokine production by human T cells in disease states. Ann Rev Immunol 1994 12:227-257.
5. Nakamura T, Kamogawa Y, Bottomly K, Flavell RA. Polarization of IL-4- and IFN-gamma-producing CD4+ T cells following activation of naive CD4+ T cells. J Immunol 1997. 158:1085-1094.
6. Bucy RP, Karr L, Huang G, Li J, Carter D, Honjo K, Lemons JA, Murphy KM, Weaver CT. Single cell analysis of cytokine gene coexpression during CD4+ T cell phenotype development. Proc Natl Acad Sci U S A 1995. 92:7565-7569.
7. Abbas AK, Murphy KM and Sher A. Functional diversity of helper T lymphocytes. Nature 1996. 383:787-793.
8. Lafaille JJ. The role of helper T cell subsets in autoimmune diseases. Cytokine Growth Factor Rev 1998. 9(2):139-151.
9. Rabinovitch A. Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM: therapeutic intervention by immunostimulation? Diabetes 1994. 43:613-621.
10. Bot A, Smith KA, von Herrath M. Molecular and cellular control of T1/T2 immunity at the interface between antimicrobial defense and immune pathology. DNA Cell Biol 2004. 23(6):341-50.
11. Hanninen A, Jalkanen S, Salmi M, Toikkanen S, Nikolakaros G, Simel O. Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest 1992. 90:1901-1910.
12. Imagawa A, Hanafusa T, Tamura S, Moriwaki M, Itoh N, Yamamoto K, Iwahashi H, Yamagata K, Waguri M, Nanmo T, et al. Pancreatic biopsy as a procedure for detecting the in situ autoimmune phenomenon in type 1 diabetes. Diabetes 2001. 50:1269-1273.
13. Berman MA, Sandborg CI, Wang Z, Imfeld KL, Zaldivar F Jr, Dadufalza V Buckingham BA. Decreased IL-4 production in new onset type 1 insulin-dependent diabetes mellitus. J Immunol 1996. 157(10):4690-4696.
14. Farilla L, Dotta F, Di Mario U, Rapoport B, McLachlan SM. Presence of interleukin 4 or interleukin 10, but not both cytokines, in pancreatic tissue of two patients with recently diagnosed diabetes mellitus type I. Autoimmunity 2000. 32(3):161-166.
15. Karlsson MG, Lawesson SS, Ludvigsson J. Th1-like dominance in high-risk first-degree relatives of type I diabetic patients. Diabetologia 2000. 43(6):742-749.
16. Karlsson Faresjo MG, Ernerudh J, Ludvigsson J. Cytokine profile in children during the first 3 months after the diagnosis of type 1 diabetes. Scand J Immunol 2004. 59(5):517-526.
17. Bendelac A, Carnaud C, Boitard C, Bach JF. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Ly2+ T cells. J Exp Med 1987. 166:823-832.
18. Miller BJ, Appel MC, O’Neil JJ, Wicker LS. Both the Lyt-2 and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J Immunol 1988. 140:52-58.
19. Chrsitianson SW, Shultz LD, Leiter EH. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T cells from diabetic versus prediabetic NOD.NON-thy-1a donors. Diabetes 1993. 43:44-55.
20. Hirai H, Kaino K, Ito T, Kida K. Analysis of cytokine mRNA expression in pancreatic islets of nonobese diabetic mice. J Pediatr Endocrinol Metab 2000. 13(1):91-98.
21. Rabinovitch A, Suarez-Pinzon WL, Sorensen O, Bleackley RC, Power RF. IFN-gamma gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice. J Immunol 1995. 154:4874-4882.
22. Rabinovitch A, Suarez-Pinzon WL, El-Sheikh A, Sorensen O, Power RF. Cytokine gene expression in pancreatic islet-infiltrating leukocytes of BB rats: expression of Th1 cytokines correlates with beta-cell destructive insulitis and IDDM. Diabetes 1996. 45:749-754.
23. Kolb H. Benign vs destructive insulitis. Diabetes Metab Rev 1997. 13:139-146.
24. Bao M, Yang Y, Jun H-S, Yoon JW. Molecular mechanisms for gender differences in susceptibility to T cell-mediated autoimmune diabetes in non-obese diabetic mice. J Immunol 2002. 168:5369-5375.
25. Marselli L, Dotta F, Piro S, Santangelo C, Masini M, Lupi R, Realacci M, del Guerra S, Mosca F, Boggi U, Purrello F, Navalesi R, Marchetti P. Th2 Cytokines Have a Partial, Direct Protective Effect on the Function and Survival of Isolated Human Islets Exposed to Combined Proinflammatory and Th1 Cytokines. J Clin Endocrinol Metab 2001. 86(10):4974-4978.
26. Laybutt DR, Kaneto H, Hasenkamp W, Grey S, Jonas JC, Sgroi DC, Groff A, Ferran C, Bonner-Weir S, Sharma A, Weir GC. Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survival during chronic hyperglycemia. Diabetes 2002. 51:413-423.
27. Murata Y, Amao M, Hamuro J. Sequential conversion of the redox status of macrophages dictates the pathological progression of autoimmune diabetes. Eur J Immunol 2003. 33(4):1001-1011.
28. Murata Y, Shimamura T, Hamuro J. The polarization of T(h)1/T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. Int Immunol 2002. 14(2):201-212.
29. Pennine KL, Roque-Gaffney E. Monahan M. Recombinant human IL-10 prevents the onset of diabetes in the NOD mouse. J Immunol Immunopathol 1995. 71:169-175.
30. Wogensen L, Haung X, Sarvetnick N. Leucocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans. J Exp Med 1993. 178:175-185.
31. Mortani M, Yoshimoto K, Tashiro F, Hashimoto C, Miyazaki JI, Ii S, Kudo E, Iwahana H, Hayashi Y, Sano T, Itakura M. Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice. Nature Immunol 1994. 6:1927-1936.
32. Pauza ME, Neal H, Hagenbaugh A, Hilde C, David L. T-cell production of an inducible interleukin-10 transgene provides limited protection from autoimmune diabetes. Diabetes 1999. 48:1948-1953.
33. Cameron MJ, Arreaza GA, Zucker P, Chensue SW, Strieter RM, Chakrabarti S, Delotvitch TL. IL-4 prevents insulitits and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol 1997. 159:4686-4692.
34. Rapoport MJ, Jaramillo A, Zipris D, Lazarus AH, Serreze DV, Leiter EH, Cyopick P, Danska JS, Delovitch TL. Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. J Exp Med 1993. 178(1):87-99.
35. Mueller R, Krahl T, Sarvetnick N. Pancreatic expression of interleukin-4 abrogate insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 1996. 184:1093-1099.
36. Gallichan WS, Blasa B, Davies JD, Sarvetnick N. Pancreatic IL-4 expression results in islet-reactive Th2 cells that inhibit diabetogenic lymphocytes in the nonobese diabetic mouse. J Immunol 1999. 163:1696-1703.
37. Pauza ME, Nguyen A, Wolfe T, Ho IC, Glimcher LH, von Herrath M, Lo D. Variable effects of transgenic c-Maf on autoimmune disbetes. Diabetes 2001. 50:39-46.
38. Rossini AA, Greiner DL, Friedman HP, Mordes JP. Immunopathogenesis of diabetes mellitus. Diabetes Rev 1993. 1:43-75
39. Shehadeh NN, LaRosa F and Lafferty KJ. Altered cytokine activity in adjuvant inhibition of autoimmune diabetes. J Autoimmun 6(3): 291-300, 1993
40. Singh B, Rabinovitch A. Influence of microbial agents on the development of autoimmune diabetes. Autoimmunity 1993. 15:209-213.
41. Harrison LC, Hafler DA. Antigen-specific therapy for autoimmune disease Curr Opin Immunol 2000. 12(6):704-711.
42. Leijon K, Hammastrom B, Holmberg D. Non-obese diabetic (NOD) mice display enhanced immune responses and prolonged survival of lymphoid cells. Int Immunol 1994. 6(2):339-345.
43. Noorchashm H, Moore DJ, Noto LE, Noorchashm N, Reed AJ, Reed AL, Song HK, Mozaffari R, Jevnikar AM, Barker CF, Naji A. Impaired CD4 T Cell Activation Due to Reliance Upon B Cell-Mediated Costimulation in Nonobese Diabetic (NOD) Mice. J Immunol 2000. 165:4685-4696.
44. Serreze DV, Chapman HD, Post CM, Johnson EA, Suarez-Pinzon WL, Rabinovitch A. Th1 to Th2 Cytokine Shifts in Nonobese Diabetic Mice: Sometimes an Outcome, Rather Than the Cause, of Diabetes Resistance Elicited by Immunostimulation. J Immunol 2001. 166:1352-1359.