Differential effects of cyclosporins A and G on functional activation of a T-helper-lymphocyte line mediating experimental autoimmune uveoretinitis.
The effect and relative efficiency of cyclosporin A (CsA) and cyclosporin G (CsG) on suppressing the activation of primed autoimmune rat T-helper lymphocytes were assayed. The autoimmune T-helper cells (ThS) are a long-term line specific to the retinal soluble antigen (SAg) and can adoptively transfer experimental autoimmune uveoretinitis (EAU), after in vitro reactivation with antigen or mitogen, to naive syngeneic hosts. Antigen-driven production of interleukin-2 (IL-2) and antigen-driven proliferation were inhibited in a dose-dependent manner and to a similar extent at each of the respective cyclosporin concentrations. CsA was 8-10 times more potent than CsG, with ID50-CsA occurring at 0.5 to 2 ng/ml, and ID50-CsG at 5 to 20 ng/ml, depending on the experiment and the cyclosporin batch. Addition of exogenous lymphokines in the form of rat spleen concanavalin A (Con A)-conditioned medium (SCM) or recombinant IL-2 (but not recombinant IL-1) was able to reverse only about half of the inhibition, as measured along the linear part of the dose-response curve. Inhibition of IL-2 production was lost if a maximally inhibitory dose of cyclosporin was added to the cultures later than 8 hr after antigen stimulation, while proliferation was still suppressed to 50% by cyclosporin added as late as 12 hr and could not be restored by addition of SCM. Both cyclosporins at concentrations that blocked proliferation and IL-2 production significantly suppressed the generation of high-affinity and low-affinity IL-2 receptors by ThS in response to antigen (as assayed by direct binding of 125I-IL-2). These results suggest that CsA and CsG inhibit antigen-induced expansion of ThS by interfering with more than one activation step. In contrast, the in vitro activation of the uveitogenic potential of ThS cells, incubated with antigen in the presence of CsA or CsG and adoptively transferred into untreated recipients, was not affected by the cyclosporins. Thus, triggering of the pathogenic potential of primed autoimmune T-helper lymphocytes can take place in the presence of cyclosporin and in the absence of cellular proliferation.
Caspi
R R
RR
Laboratory of Immunology, National Institutes of Health, Bethesda, Maryland 20896.
McAllister
C G
CG
Gery
I
I
Nussenblatt
R B
RB
D000818:Animals; D000941:Antigens / Q000276:immunology*; D019393:Arrestin; D001327:Autoimmune Diseases / Q000276:immunology; D016572:Cyclosporine; D003524:Cyclosporins / Q000494:pharmacology*; D005136:Eye Proteins / Q000276:immunology*; D007165:Immunosuppression Therapy; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008211:Lymphocyte Cooperation / Q000187:drug effects; D010870:Pineal Gland / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D011971:Receptors, Immunologic / Q000378:metabolism; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins / Q000494:pharmacology; D012173:Retinitis / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014605:Uveitis / Q000276:immunology*
D000941:Antigens; D019393:Arrestin; D003524:Cyclosporins; D005136:Eye Proteins; D007375:Interleukin-1; D007376:Interleukin-2; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; C045571:cyclosporin G; D016572:Cyclosporine