Effector mechanisms in cyclosporine A-induced syngeneic graft-versus-host disease

Role of CD4+ and CD8+ T lymphocyte subsets

Allan D. Hess, Anne C. Fischer, William E. Beschorner

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Syngeneic graft-versus-host disease (SGVHD) is a T cell-mediated autoimmune disease occurring postsyngeneic bone marrow transplantation and the administration of the potent immunosuppressive agent, cyclosporine A. Paradoxically, cyclosporine A disrupts the immunologic homeostasis governing self-tolerance. Our studies using an adoptive transfer model attempted to identify effector mechanisms associated with the autoimmune disease. Both CD4+ and CD8+ splenic T cells isolated from autoimmune donors were required for the adoptive transfer of active disease into lethally irradiated secondary recipients reconstituted with normal bone marrow. Doses of more than 5 × 106 of nylon wool depleted splenocytes from autoimmune donors effectively transferred disease into lethally irradiated secondary recipients. Splenocytes that are T cell depleted or CD4+-enriched cells did not elicit disease upon adoptive transfer. Nylon wool fractionated CD8+ splenocytes also failed to adoptively transfer disease unless high doses (≥30 × 106) were used. The disease transferred with the CD8+ subset presented as acute type SGVHD and was self-limiting. The recombination of the individually isolated T cell subsets not only restored but also enhanced immune reactivity upon adoptive transfer. Moreover, use of the recombined subsets resulted in progressive disease with the development of chronic type SGVHD. The titration of each subset to the other suggested that a minimal number of CD4+ T cells was required to potentiate the CD8+ autoreactive cells in vivo. Further analysis of the helper cell involved demonstrated that it had a CD4+ CD45r- phenotype, characteristic of an amplifying helper cell population. Administration of IL-2 did not substitute for CD4+ Th cells but yet amplified the activity of unfractionated cells or recombined subsets implicating the role of other factors in the pathogenesis of SGVHD. Delineation of the effector mechanisms involved in SGVHD is critical in determining the underlying events that trigger either the production of autoreactive cells or the perturbation of the regulation of these autoreactive cells, culminating in autoimmunity.

Original languageEnglish (US)
Pages (from-to)526-533
Number of pages8
JournalJournal of Immunology
Volume145
Issue number2
StatePublished - Jul 15 1990

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T-Lymphocyte Subsets
Graft vs Host Disease
Cyclosporine
Adoptive Transfer
T-Lymphocytes
Wool
Nylons
Helper-Inducer T-Lymphocytes
Autoimmune Diseases
Self Tolerance
Immunosuppressive Agents
Bone Marrow Transplantation
Autoimmunity
Genetic Recombination
Interleukin-2
Homeostasis
Bone Marrow
Phenotype
Population

ASJC Scopus subject areas

  • Immunology

Cite this

Effector mechanisms in cyclosporine A-induced syngeneic graft-versus-host disease : Role of CD4+ and CD8+ T lymphocyte subsets. / Hess, Allan D.; Fischer, Anne C.; Beschorner, William E.

In: Journal of Immunology, Vol. 145, No. 2, 15.07.1990, p. 526-533.

Research output: Contribution to journalArticle

Hess, Allan D. ; Fischer, Anne C. ; Beschorner, William E. / Effector mechanisms in cyclosporine A-induced syngeneic graft-versus-host disease : Role of CD4+ and CD8+ T lymphocyte subsets. In: Journal of Immunology. 1990 ; Vol. 145, No. 2. pp. 526-533.
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