Laboratory Investigation

Kidney International (1997) 51, 94–103; doi:10.1038/ki.1997.12

Th1 responsiveness to nephritogenic antigens determines susceptibility to crescentic glomerulonephritis in mice

Xiao-Ru Huang1, Peter G Tipping1, Li Shuo1 and Stephen R Holdsworth1

1Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

Correspondence: Dr P G Tipping, Department of Medicine, Monash Medical Centre, 246 Clayton Rd., Clayton, 3168 Victoria, Australia.

Received 22 May 1996; Revised 25 July 1996; Accepted 25 July 1996.

Top

Abstract

Th1 responsiveness to nephritogenic antigens determines susceptibility to crescentic glomerulonephritis in mice. The pattern of glomerulonephritis (GN) developing in response to a planted antigen (sheep anti-mouse GBM globulin) was compared in two strains of mice which demonstrated either a predominant Th1 (C57BL/6) or Th2 (BALB/c) response to this antigen. GN was induced with a subnephritogenic i.v. dose of sheep anti-mouse GBM globulin in mice presensitized to sheep globulin. Sensitized C57BL/6 mice showed pronounced cutaneous delayed-type hypersensitivity (DTH) following the challenge with sheep globulin, low titers of circulating anti-sheep globulin antibody and high interferon gamma (IFNgamma) and low interleukin 4 (IL-4) production by splenic T cells, consistent with a predominant Th1 pattern of immune response. Sensitized BALB/c mice did not develop DTH following cutaneous challenge with sheep globulin, had higher circulating anti-sheep globulin antibody titers, and showed high IL-4 and low IFNgamma production by splenic T cells compared with C57BL/6 mice, consistent with a predominant Th2 response. In C57BL/6 mice, GN developing in response to sheep globulin exhibited a severe crescentic pattern with prominent glomerular T cell and macrophage influx and fibrin deposition. In vivo depletion with a monoclonal anti-CD4 antibody demonstrated that this injury was T helper cell dependent. Treatment with monoclonal anti-mouse IFNgamma antibody significantly reduced glomerular injury and crescent formation and attenuated the cutaneous DTH response. GN induced by the same protocol in BALB/c mice exhibited pronounced glomerular IgG and complement deposition. Crescent formation, fibrin deposition, and glomerular T cell and macrophage infiltration were significantly less than observed in C57BL/6 mice, and injury was not T cell dependent in the effector phase. These data suggest that the pattern of glomerular injury induced by a planted antigen can be determined by the balance of T helper cell subset activation. A Th1 response induces a severe crescentic pattern of GN, which like cutaneous DTH, is T helper cell and IFNgamma dependent.

Abbreviations:

DTH, delayed type hypersensitivity; GBM, glomerular basement membrane; GN, glomerulonephritis; c/gcs, cells per glomerular cross-section

Top

References

  1. Tipping PG, Neale TJ, Holdsworth SR: T lymphocyte participation in antibody induced experimental glomerulonephritis. Kidney Int 27:530–537, 1985 | PubMed | ISI | ChemPort |
  2. Boyce NW, Tipping PG, Holdsworth SR: Lymphokine (MIF) production by glomerular T-lymphocytes in experimental glomerulonephritis. Kidney Int 30:673–677, 1986 | PubMed | ISI | ChemPort |
  3. Oite T, Shimizu F, Kagami S, Morioka T: Hapten-specific cellular immune response producing glomerular injury. Clin Exp Immunol 76:463–468, 1989
  4. Bhan AK, Schneeberger EE, Collins AD, McCluskey RT: Evidence for a pathogenic role for a cell mediated immune mechanism in experimental glomerulonephritis. J Exp Med 148:246–260, 1978 | Article | PubMed | ISI | ChemPort |
  5. Bhan AK, Collins AB, Schneeberger EE, McCluskey RT: A cell mediated reaction against glomerular bound immune complexes. J Exp Med 148:246–260, 1979
  6. Bolton WK, Chandra M, Tyson TM, Kirkpatrick PR, Sadovnic MJ, Sturgill BC: Transfer of experimental glomerulonephritis in chickens by mononuclear cells. Kidney Int 34:598–610, 1988 | PubMed | ISI | ChemPort |
  7. Huang XR, Holdsworth SR, Tipping PG: Evidence for delayed-type hypersensitivity mechanisms in glomerular crescent formation. Kidney Int 46:69–78, 1994 | PubMed | ISI | ChemPort |
  8. Kawasaki K, Yaoita E, Yamamoto T, Kihara I: Depletion of CD8 positive cells in nephrotoxic serum nephritis of WKY rats. Kidney Int 41:1517–1526, 1992 | PubMed | ISI | ChemPort |
  9. Bolton WK, Innes DJ Jr, Sturgill BC, Kaiser DL: T-cells and macrophages in rapidly progressive glomerulonephritis: Clinicopath-ologic correlations. Kidney Int 32:869–876, 1987 | PubMed | ISI | ChemPort |
  10. Nolasco FE, Cameron JS, Hartley B, Coelho A, Hildreth G, Reuben R: Intraglomerular T cells and monocytes in nephritis: Study with monoclonal antibodies. Kidney Int 31:1160–1166, 1987 | PubMed | ISI | ChemPort |
  11. Neale TJ, Tipping PG, Carson SD, Holdsworth SR: Participation of cell-mediated immunity in deposition of fibrin in glomerulonephritis. Lancet 2:421–424, 1988 | Article | PubMed | ChemPort |
  12. Stachura I, Si L, Whiteside TL: Mononuclear cell subsets in human idiopathic crescentic glomerulonephritis (ICGN): Analysis in tissue sections with monoclonal antibodies. J Clin Immunol 4:202–208, 1984 | Article | PubMed | ISI | ChemPort |
  13. Stilman MM, Bolton WK, Sturgill BC, Schmitt GW, Couser WG: Crescentic glomerulonephritis without immune deposits. Clini-copathological features. Kidney Int 15:184–195, 1979
  14. Mosmann TR, Coffman RL: Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol 46:111–147, 1989 | PubMed | ISI | ChemPort |
  15. Cher DJ, Mosmann TR: Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol 138:3688–3694, 1987 | PubMed | ISI | ChemPort |
  16. Fong TA, Mosmann TR: The role of IFN-gamma in delayed-type hypersensitivity mediated by Th1 clones. J Immunol 143:2887–2893, 1989 | PubMed | ISI | ChemPort |
  17. Mocci S, Coffman RL: Induction of a Th2 population from a polarized Leishmania-specific Th1 population by in vitro culture with IL-4. J Immunol 154:3779–3787, 1995 | PubMed | ISI | ChemPort |
  18. Li L, Elliott JF, Mosmann TR: IL-10 inhibits cytokine production, vascular leakage and swelling during T helper cell-induced delayed-type hypersensitivity. J Immunol 153:3967–3977, 1994 | PubMed | ISI | ChemPort |
  19. Gajewski TF, Fitch FW: Anti-proliferative effect of IFNy in immune regulation. I. IFNy inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol 140:4245–4252, 1988 | PubMed | ISI | ChemPort |
  20. Sadick MD, Heinzel FP, Shigekane VM, Fisher WL, Locksley RM: Cellular and humoral immunity to Leishmania major in genetically susceptible mice after in vivo depletion of L3T4+ T cells. J Immunol 139:1303–1309, 1987
  21. Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM: Reciprocal expression of interferon gamma or interleukin 4 during resolution or progression of murine Leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med 169:59–72, 1989 | Article | PubMed | ISI | ChemPort |
  22. Liblau RS, Singer SM, McDevitt HO: Th1 and Th2 CD4-T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 16:34–38, 1995 | Article | PubMed | ISI | ChemPort |
  23. Tipping PG, Huang XR, Berndt MC, Holdsworth SR: A role for P selectin in complement-independent neutrophil-mediated glomerular injury. Kidney Int 46:79–88, 1994 | PubMed |
  24. Tipping PG, Huang XR, Berndt MC, Holdsworth SR: P-selectin directs T lymphocyte mediated injury in delayed type hypersensitivity responses: Studies in glomerulonephritis and cutaneous delayed type hypersensitivity. Eur J Immunol 26:454–460, 1996 | PubMed |
  25. Bradford MM: A rapid and sensitive method for quantitation of microgram quantities of protein utilising the principle of protein-dye binding. Anal Biochem 72:248–254, 1976 | Article | PubMed | ISI | ChemPort |
  26. Spitalny GL, Havell EA: Monoclonal antibody to murine gamma interferon inhibits lymphokine-induced antiviral and macrophage tumoricidal activities. J Exp Med 159:1560–1565, 1984 | Article | PubMed | ChemPort |
  27. Wofsy D, Seaman WE: Successful treatment of autoimmunity in NZB/NZW Fl mice with monoclonal antibody to L3T4. J Exp Med 161:378–391, 1985 | Article | PubMed | ISI | ChemPort |
  28. Ranges GE, Sriram S, Cooper SM: Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4. J Exp Med 162:1105–1110, 1985 | Article | PubMed | ISI | ChemPort |
  29. Belosevic M, Finbloom DS, van der Meide PH, Slayter MV, Nacy CA: Administration of anti-IFNy antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol 143:266–274, 1989 | PubMed | ChemPort |
  30. Duong TT, Finkelman FD, Singh S, Strejan GH: Effect of anti interferon-gamma monoclonal antibody treatment on the development of experimental allergic encephalomyelitis in resistant mice strains. J Neuroimmunol 53:101–107, 1994 | Article | ChemPort |
  31. Boissier M-C, Chiocchia G, Bessis N, Hajnal J, Garotta G, Nicoletti F, Fournier C: Biphasic effect of interferon-gamma in murine collagen-induced arthritis. Eur J Immunol 25:1184–1190, 1995 | PubMed | ChemPort |
  32. Koyama A, Inage H, Kobayashi M, Narita M, Tojo S: Effect of chemical cationization of antigen on glomerular localization of immune complexes in active models of serum sickness nephritis in rabbits. Immunology 58:535–540, 1986
  33. Golbus SM, Wilson CB: Experimental glomerulonephritis induced by in situ formation of immune complexes in glomerular capillary wall. J Clin Invest 16:148–157, 1979
  34. Campbell IL, Kay TWH, Oxbrow L, Harrison L: Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. J Clin Invest 87:739–742, 1991 | PubMed | ISI | ChemPort |
  35. Debray-Sachs M, Carnaud C, Boitard C, Cohen H, Gresser I, Bedossa P, Bach JF: Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma. J Autoimmun 4:237–248, 1991 | Article | PubMed | ChemPort |
  36. Ozmen L, Roman D, Fountoulakis M, Schmid G, Ryffel B, Garotta G: Experimental therapy of systemic lupus erythematosus: The treatment of NZB/W mice with soluble interferon-gamma receptor inhibits the onset of glomerulonephritis. Eur J Immunol 25:6–12, 1995 | PubMed | ISI | ChemPort |

Extra navigation

.
ADVERTISEMENT