Organ-Specific Hematopoietic Changes Induced by a Recombinant Human Interferon-{alpha} in Mice

Organ-Specific Hematopoietic Changes Induced by a RecombinantHuman Interferon- in Mice. ROSENTHAL, G. J., STRANAHAN, R. P.,ILL, THOMPSON, M., BLAIR, P., GERMOLEC, D. R., COMMENT, C. E.,SCHWAB, K., AND LUSTER, M. I. (1990). Fundam. Appl. Toxicol.14, 666–675. Interferon-a (IFN-) is a naturally occurringcytokine that mediates numerous biological activities and hasdemonstrated therapeutic potential in a variety of malignancies.Encouraging activity against HIV-1 replication has also beenobserved with IFN- in the treatment of AIDS, although hematotoxicityhas been a frequently observed side effect. In addition, invitro studies have suggested that IFN- may function as a down-regulatorof myelopoiesis. A recombinant hybrid of subtypes of human IFN-,rHuIFN-A/D, has antiviral activity in mu-rine cells in vitroand In vivo. This study examines the effect of acute and subchronicexposure to rHuIFN-A/D on hemopoietic and immune parametersin C57B1/6 mice. IFN-a was administered ip at 0, 1000, 10,000,and 100,000 units/day for either 1 or 10 consecutive days. Manyof the known effects of IFN- in humans such as anemia, leukopenia,and thrombocytopenia were observed in mice following subchronicexposure, with the latter two effects also manifested followingacute exposure. Further analysis showed that this leukopeniawas not selective. Both splenic and bone marrow cells were examinedfollowing 10 days of dosing with the high dose of IFN-. Lymphocyteswere reduced in both compartments, while granulocytes were increasedin both compartments. Bone marrow cells programmed to differentiateinto granulocytes (CFU-G) were suppressed, while macrophageprogenitors (CFU-M) were stimulated. Erythroid cells decreasedin the marrow but increased in the spleen, suggesting that themicroenvironmerit may play a significant role in the effectof IFN-. The proliferative capacity of both B and T spleniclymphocytes was significantly suppressed in a dose-related fashionfollowing multiple exposure to IFN-a. Clinically, IFN-a is mostoften given in multiple doses and the present data suggest thatsuch a regimen is toxic to both erythroid and myeloid cells,as well as being immunotoxic to splenic B and T lymphocytes.