Skip to main content
SpringerLink
Log in

Experimental allergic orchitis in mice. V. Resistance to actively induced disease in BALB/cJ substrain mice is mediated by CD4 + T cells

  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Previous studies have shown that differential susceptibility to actively induced experimental allergic orchitis (EAO) exists among various BALB/c substrains. Of 13 substrains studied, BALB/cJ mice consistently exhibit greater resistance to disease induction. Such resistance is associated with a single recessive genotypic difference in an immunoregulatory locus which is unlinked to any of the known alleles distinguishing the BALB/cJ substrain. In this study, gene complementation protocols were used to study the genetics of susceptibility and resistance to EAO. The results indicate that resistance in BALB/cJ mice is not due to a mutation in theH-2D d linked gene which governs the phenotypic expression of autoimmune orchitis. The mechanistic basis for disease resistance was examined using reciprocal bone marrow radiation chimeras generated between the disease-susceptible BALB/ cByJ (ByJ) substrain and BALB/cJ (Jax) mice. All constructs, including Jax →- Jax and Jax →- ByJ, developed severe EAO following inoculation with mouse testicular homogenate (MTH) and adjuvants whereas control chimeras immunized with adjuvants alone did not. These results suggest that an active immunoregulatory mechanism rather than a passive one, such as the lack of T cells and/or B cells with receptors for the aspermatogenic autoantigens relevant in the induction of EAO, is responsible for disease resistance in BALB/cJ mice. The role of immunoregulatory cells was examined by pretreating BALB/cJ mice with either cyclophosphamide (20 mg/kg) or low-dose whole body or total lymphoid irradiation (350 rads) 2 days prior to inoculation. BALB/cJ mice immunized with MTH plus adjuvants generate immunoregulatory spleen cells (SpCs) that, when transferred to naive BALB/cByJ recipients, significantly reduce the severity of autoimmune orchitis observed during actively induced EAO. Treatment of such cells with either cytotoxic monoclonal anti-Thy-1.2 or anti-CD4 plus C' before transfer abrogates the ability of BALB/cJ spleen cells to inhibit disease. In contrast, neither SpCs from adjuvantimmunized BALB/cJ nor MTH plus adjuvant-primed BALB/cByJ donors significantly influenced the severity of disease observed in recipients. Taken together, these results suggest that genetically controlled resistance to EAO in BALB/cJ mice is associated with a mutation in an immunoregulatory locus whose effects appear to be mediated through a cyclophosphamide and low-dose radiation-sensitive CD4+ T-cell population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Arnon, R.: Experimental allergic encephalomyelitis-susceptibility and suppression.Immunol Rev 55: 5–30, 1981

    PubMed  Google Scholar 

  • Bernard, C. C. A.: Experimental autoimmune encephalomyelitis in mice: genetic control of susceptibility.J Immunogenet 3: 263–274, 1976

    PubMed  Google Scholar 

  • Bernard, C. C. A.: Suppressor T cells prevent experimental autoimmune encephalomyelitis in mice.Clin Exp Immunol 29: 100–109, 1977

    PubMed  Google Scholar 

  • Bruce, J., Symington, F. W., McKearn, T. J., and Sprent, J.: A monoclonal antibody discriminating between subsets of T and B cells.J Immunol 127: 2496–2501, 1981

    PubMed  Google Scholar 

  • Ceredig, R., Lowenthal, J. W., Nabholz, M., and MacDonald, H. R.: Expression of interleukin-2 receptors as a differentiation marker on intrathymic stem cells.Nature 314: 98–100, 1985

    PubMed  Google Scholar 

  • Chiorazzi, N., Fox, D. A., and Katz, D. H.: Hapten-specific IgE antibody responses in mice. VI. Selective enhancement of IgE antibody production by low doses of X-irradiation and by cyclophosphamide.J Immunol 117: 1629–1637, 1976

    PubMed  Google Scholar 

  • Chiorazzi, N., Fox, D. A., and Katz, D. H.: Hapten specific IgE antibody responses in mice. VII. Conversion of IgE “nonresponder” strains to IgE “responders” by elimination of suppressor T-cell activity.J Immunol 118: 48–54, 1977

    PubMed  Google Scholar 

  • Ellerman, K. E., Powers, J. M., and Brostoff, S. W.: A suppressor Tlymphocyte cell line for autoimmune encephalomyelitis.Nature 331: 265–267, 1988

    PubMed  Google Scholar 

  • Hall, B. M., Pearce, N. W., Gurley, K. E., and Dorsch, S. E.: Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action.J Exp Med 171: 141–157, 1990

    PubMed  Google Scholar 

  • Hickey, W. F., Kirby, W. M., and Teuscher, C.: BALB/c substrain differences in susceptibility to experimental allergic encephalomyelitis (EAE).Ann NY Acad Sci 475: 331–333, 1986

    Google Scholar 

  • Hiramine, C. and Hojo, K.: Adoptive transfer of suppression of experimental allergic orchitis with lymphoid cells from antigenpretreated guinea pigs.Clin Immunol Immunopathol 30: 202–213, 1984

    PubMed  Google Scholar 

  • Janeway, C. A., Jr., Carding, S., Jones, B., Murray, J., Portoles, P., Rasmussen, R., Rojo, J., Saizawa, K., West, J., and Bottomly, K.: CD4+ T cells: specificity and function.Immunol Rev 101: 39–80, 1988

    PubMed  Google Scholar 

  • Karpus, W. J. and Swanborg, R. H.: CD4+ suppressor cells differentially affect the production of IFN-γ by effector cells of experimental autoimmune encephalomyelitis.J Immunol 143: 3492–3497, 1989

    PubMed  Google Scholar 

  • Kohno, S., Munoz, J. J., Wiliams, T. M., Teuscher, C., Bernard, C. C. A., and Tung, K. S. K.: Immunopathology of murine experimental allergic orchitis.J Immunol 130: 2675–2682, 1983

    PubMed  Google Scholar 

  • Kong, Y. M., Giraldo, A. A., Waldmanm, H., Cobbold, S. P., and Fuller, B. E.: Resistance to experimental autoimmune thyroiditis: L3T4- cells as mediators of both thyroglobulin-activated and TSH induced suppression.Clin Immunol Immunopathol 51: 38–54, 1989

    PubMed  Google Scholar 

  • Korngold, R., Feldman, A., Rorke, L. B., Lublin, F. D., and Doherty, P. C.: Acute experimental allergic encephalomyelitis in radiation bone marrow chimeras between high and low susceptible strains of mice.Immunogenetics 24: 309–315, 1986

    PubMed  Google Scholar 

  • Lando, Z., Teitelbaum, D., and Arnon, R.: Genetic control of susceptibility to experimental allergic encephalomyelitis in mice.Immunogenetics 9: 435–442, 1979a

    Google Scholar 

  • Lando, Z., Teitelbaum, D., and Arnon, R.: Effect of cyclophosphamide on suppressor cell activity in mice unresponsive to EAE.J Immunol 123: 2156–2160, 1979b

    PubMed  Google Scholar 

  • Lando, Z., Teitelbaum, D., and Arnon, R.: Induction of experimental allergic encephalomyelitis in genetically resistant strains of mice.Nature 287: 551–552, 1980

    PubMed  Google Scholar 

  • Linthicum, D. S. and Frelinger, J. A.: Acute autoimmune encephalomyelitis in mice. II. Susceptibility is controlled by the combination of H-2 and histamine sensitization genes.J Exp Med 156: 31–40, 1982

    PubMed  Google Scholar 

  • Mahi-Brown, C. A. and Tung, K. S. K.: Susceptibility to experimental autoimmune orchitis (EAO) can be adoptively transferred from responder to non-responder substrains of BALB/c mice.Biol Reprod 38 (Suppl 1): 82, 1988

    Google Scholar 

  • Mahi-Brown, C. A. and Tung, K. S. K.: Activation requirements of donor T cells and host T cell recruitment in adoptive transfer of murine experimental autoimmune orchitis (EAO).Cell Immunol 124: 368–379, 1989

    PubMed  Google Scholar 

  • Mahi-Brown, C. A., Yule, T. D., and Tung, K. S. K.: Adoptive transfer of marine autoimmune orchitis to naive recipients with immune lymphocytes.Cell Immunol 106: 408–419, 1987

    PubMed  Google Scholar 

  • McDonald, A. H. and Swanborg, R. H.: Antigen-specific inhibition of immune interferon production by suppressor cells of autoimmune encephalomyelitis.J Immunol 140: 1132–1138, 1988

    PubMed  Google Scholar 

  • Mossman, T. R. and Coffman, R. L.: TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.Annu Rev Immunol 7: 145–173, 1989

    PubMed  Google Scholar 

  • Munoz, J. J. and Mackay, I. R.: Production of experimental allergic encephalomyelitis with the aid of pertussigen in mouse strains considered genetically resistant.J Neuroimmunol 7: 91–96, 1984

    PubMed  Google Scholar 

  • Padberg, W. M., Kupiec-Weglinski, J. W., Lord, R. H. H., Araneda, D. H., and Tilney, N. L.: W3/25+ T cells mediate the induction of immunologic unresponsiveness in enhanced rat recipients of cardiac allografts.J Immunol 138: 3669–3674, 1987

    PubMed  Google Scholar 

  • Potter, M.: History of the BALB/c family.Curr Top Microbiol Immunol 122: 1–5, 1985

    Google Scholar 

  • Sarmiento, M., Glasebrook, A. L., and Fitch, F. W.: IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt antigen block T-cell-mediated cytolysis in the absence of complement.J Immunol 125: 2665–2672, 1980

    PubMed  Google Scholar 

  • Sprent, J., Schaefer, M., Gao, E.-K., and Korngold, R.: Role of T cell subsets in lethal graft-versus-host disease (GVHD) directed to class I versus class II H-2 differences. I. L3T4÷ cells can either augment or retard GVHD elicited by Lyt-2+ cells in class I-different hosts.J Exp Med 167: 556–569, 1988

    PubMed  Google Scholar 

  • Teuscher, C.: Experimental allergic orchitis in mice. II. Association of disease susceptibility with the locus controllingBordetella pertussis-induced sensitivity to histamine.Immunogenetics 22: 417–425, 1985

    PubMed  Google Scholar 

  • Teuscher, C., Potter, M., and Tung, K. S. K.: Differential susceptibility to experimental autoimmune orchitis in BALB/c substrains.Curr Top Microbiol Immunol 122: 181–188, 1985a

    PubMed  Google Scholar 

  • Teuscher, C., Smith, S. M., Goldberg, E. H., Shearer, G. M., and Tung, K. S. K.: Experimental allergic orchitis in mice. I. Genetic control of susceptibility and resistance to induction of autoinunune orchitis.Immunogenetics 22: 323–333, 1985b

    PubMed  Google Scholar 

  • Teuscher, C., Smith, S. M., and Tung, K. S. K.: Experimental allergic orchitis in mice. III. Differential susceptibility and resistance among BALB/c sublines.J Reprod Immunol 10: 219–230, 1987a

    PubMed  Google Scholar 

  • Teuscher, C., Blankenhorn, E. P., and Hickey, W. F.: Differential susceptibility to actively induced experimental allergic encephalomyelitis and experimental allergic orchitis among BALB/c substrains.Cell Immunol 110: 294–304, 1987b

    PubMed  Google Scholar 

  • Teuscher, C., Blankenhorn, E. P., and Hickey, W. F.: Genetic analysis of BALB/cJ subline resistance to actively induced experimental allergic orchitis (EAO) and experimental allergic encephalomyelitis (EAE).Curr Top Microbiol Immunol 137: 233–239, 1988

    PubMed  Google Scholar 

  • Tite, J. P., Foellmer, H. G., Madri, J. A., and Janeway, C. A., Jr.: Inverse Ir gene control of antibody and T cell proliferative responses to human basement membrane collagen.J Immunol 139: 2892–2898, 1987

    PubMed  Google Scholar 

  • Yule, T. D., Montoya, G. D., Russell, L. D., Williams, T. M., and Tung, K. S. K.: Autoantigenic germ cells exist outside the blood testis barrier.J Immunol 141: 1161–1167, 1988

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Reproductive Biology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Cory Teuscher

  2. Department of Pathology and Laboratory Medicine, Washington University, St. Louis, Missouri, USA

    William F. Hickey

  3. Department of Microbiology and Immunology, Jefferson Medical College, Philadelphia, Pennsylvania, USA

    Robert Korngold

Authors
  1. Cory Teuscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William F. Hickey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert Korngold
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Teuscher, C., Hickey, W.F. & Korngold, R. Experimental allergic orchitis in mice. V. Resistance to actively induced disease in BALB/cJ substrain mice is mediated by CD4 + T cells. Immunogenetics 32, 34–40 (1990). https://doi.org/10.1007/BF01787326

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01787326

Keywords

Search

Navigation