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Specific Immunosuppressive Effects of Constant Infusion of 2'-Deoxycoformycin¹

Laboratories of Cell Metabolism [P. P. T., A. T., M. E. B.] and Immunobiology [S. I., R. P., R. A. G.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

The effect of continuous infusion into C57BL/6J mice of 2'-deoxycoformycin (DCF), a tight-binding inhibitor of adenosine deaminase, on the biological function of bone marrow stem cells and T- and B-lymphocytes was evaluated. Greater than 85% inhibition of adenosine deaminase in erythrocytes, thymus, and bone marrow was noted after DCF infusion at 0.4 mg per kg body weight per day, while lesser extents of inhibition were characteristic of spleen and lymph nodes. The reconstitution of lethally irradiated C57BL/6J mice with bone marrow cells from DCF- and 0.9% NaCl infused mice of the same strain was compared. The two groups of animals were virtually identical with respect to (a) the number of spleen colony-forming units, (b) the response of splenic lymphocytes to both B- and T-cell mitogens, (c) hematological analysis of peripheral blood elements, and (d) survival time, thus strongly supporting a lack of effect of DCF infusion on the capacity of stem cells to differentiate. In contradistinction, DCF infusion was highly lymphocytotoxic as noted by the severe necrosis in both B- and T-cell regions in lymph nodes and spleen and by the dramatic weight reduction in spleen and thymus. Histopathology of other tissues including bone marrow was normal except for the occurrence of hepatitis. A striking decrease in blastogenesis induced by the mitogens concanavalin A, phytohemagglutinin, and Escherichia coli lipopolysaccharides was also observed after DCF infusion. Consistent with these data, in vitro incubation of bone marrow cells with DCF did not impaire the number of spleen colony-forming units produced in lethally irradiated mice. These data suggest a potential use for adenosine deaminase inhibitors in the prevention of graft-versus-host disease in hematopoietic transplantation.

¹ This research was supported by USPHS Grant CA-14906 from the National Cancer Institute through the National Large Bowel Cancer Project; USPHS Grants CA-08748, CA-17404, and AI-11843; the National Foundation March of Dimes; and the Zelda Radow Weintraub Foundation.

² Recipient of American Cancer Society Faculty Research Award FRA-182. To whom all correspondence should be addressed.

³ Present address: Clinica Medica Università Di Medicina, Cagliari, Italy.

Received 10/24/80. Accepted 2/23/81.