Ljj. Beijleveld et al., SUSCEPTIBILITY TO CLINICALLY MANIFEST CYCLOSPORINE-A (CSA)-INDUCED AUTOIMMUNE-DISEASE IS ASSOCIATED WITH INTERFERON-GAMMA (IFN-GAMMA)-PRODUCING CD45RC(-) T-HELPER CELLS() RT6(), Clinical and experimental immunology, 105(3), 1996, pp. 486-496
Lethally irradiated Lewis (LEW) rats reconstituted with syngeneic bone
marrow and given CsA for a 4-week period, develop, upon withdrawal of
CsA, a graft-versus-host-like disease, so-called CsA-induced autoimmu
nity (CsA-AI). This T cell-mediated autoimmune disease is thymus-depen
dent; it is generally held that this disease is a consequence of aberr
ant T cell recovery brought about by CsA. In this study we determined
mononuclear cell subsets phenotypically by tri-colour flow cytometry.
A strong decrease in recent thymic emigrants (Thy1.1(+), TCR alpha bet
a(+)) was observed as a consequence of CsA treatment, eventually resul
ting in decreased absolute peripheral T cell numbers. In these rats no
altered CD4:CD8 T cell ratio was observed before onset of CsA-AI; CD4
(+) and CD8(+) cells consisted predominantly of monocytes (CD4(dim+),
TCR alpha beta(-)) and natural killer cells (CD8(+), TCR alpha beta(-)
), respectively. LEW rats, x-irradiated, syngeneic bone marrow-reconst
ituted and treated with CsA, showed a marked and persistent, relative
expansion of mature CD45RC(+), RT6(-) Th cells. In contrast, Brown-Nor
way rats treated in a similar fashion, or LEW rats subjected to either
CsA treatment or x-irradiation, did not show a comparable expansion o
f mature CD45RC(+), RT6(-) Th cells, nor did these animals develop CsA
-AI. The CD45RC(+), RT6(-) Th cells produced IL-2, and moreover consti
tuted the only Th subset producing IFN-gamma upon stimulation, and the
refore were considered as Th1-like effector cells. These results are c
onsistent with the view that a persistent preponderance of Th1 cells a
nd not the mere presence of autoreactive cells determines whether or n
ot clinically manifest CsA-AI will occur.