Selective inhibition of T cell activation by an inhibitor of S-adenosyl-L-homocysteine hydrolase.
Defects in the enzymes involved in the pathway of S-adenosylmethionine (AdoMet) metabolism, or inhibition of those enzymes, results in profound immunodeficiency. We have examined MDL 28,842, a novel irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase (AdoHcyase), an enzyme involved in AdoMet metabolism, to determine its effect on the immune system and to investigate its potential as an immunosuppressive agent. The stimulation of human mononuclear cell proliferation in vitro with Con A, a T cell mitogen, and PWM, a T-dependent B cell mitogen, were inhibited by MDL 28,842. The 50% inhibitory concentration for both were 0.33 microM. In murine spleen cells, MDL 28,842 was a potent, nontoxic, inhibitor of Con A-stimulated T cell proliferation (IC50 = 0.19 microM) but did not affect LPS-induced B cell proliferation. This selective suppression was also observed when enriched murine T and B cells were stimulated with mitogens, although S-adenosyl-L-homocysteine (AdoHcy), the substrate of AdoHcyase, was similarly elevated in both populations. In addition to proliferation in response to a number of stimuli, IL-2 production and the expression of IL-2R by mitogen-stimulated T cells were inhibited by MDL 28,842. These results suggest a direct effect of MDL 28,842 on T cells. In vivo, the antibody response to a T cell-dependent Ag, OVA, was inhibited by MDL 28,842. The response of splenic T cells from these animals to OVA in vitro were similarly depressed compared with controls. The results demonstrate that MDL 28,842 is a potent nontoxic immunosuppressive agent, which has selectivity for T cells and therefore may be useful in the treatment of T cell-mediated disorders, such as autoimmune disease and tissue transplantation.
Wolos
J A
JA
Dept. of Immunology, Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
Frondorf
K A
KA
Davis
G F
GF
Jarvi
E T
ET
McCarthy
J R
JR
Bowlin
T L
TL
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000172:deficiency; D043383:Adenosylhomocysteinase; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D015375:Receptors, Interleukin-2 / Q000032:analysis; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; C065189:4',5'-didehydro-5'-deoxy-5'-fluoroadenosine; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000243:Adenosine Deaminase; D000241:Adenosine