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Reversal of the in Vitro Methotrexate Suppression of Cell-mediated Immune Response by Folinic Acid and Thymidine plus Hypoxanthine¹

Department of Experimental Therapeutics, New York State Department of Health, Roswell Park Memorial Institute, Buffalo, New York 14263

The development of a primary complement-independent cellular cytotoxic immune response in culture by C57BL/6J spleen cells stimulated with X-irradiated allogeneic P815 tumor cells was inhibited more than 50% in the presence of 1.5 x 10^-8 M methotrexate. This immunosuppression by methotrexate was time and dose dependent. Equimolar folinic acid administered at either -4, 0, +4, or +24 hr relative to 1.5 x 10^-8 M methotrexate reversed immunosuppression by more than 50%. Increased folinic acid concentration (5 to 10-fold) completely restored the immune response only if added 4 hr prior to methotrexate. Thymidine plus hypoxanthine (100 µM each) when present throughout the 4-day culture period gave total reversal of immunosuppression. The reversal was also obtained with hypoxanthine alone and was dose dependent. These results indicate that reversal of the methotrexate-induced impairment of cellular immune function depends on several parameters including the concentration of methotrexate and of the reversing agents as well as the time of exposure of relevant target cells to these agents.

¹ These studies were supported in part by USPHS Grant CA 15142 and F32-CA 05972.

² Present address: Center for Chemical Hazard Assessment, Syracuse Research Corp., Merrill Lane, Syracuse, N. Y. 13210.

³ To whom requests for reprints should be addressed.

Received 8/20/79. Accepted 12/ 3/79.