Implications of the Analogy between Recombinant Cytokine Toxicities and Manifestations of Hantavirus Infections

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Abstract
The etiologic hantavirus of the 1993 emergence of an acute pulmonary failure syndrome in the area around northwestern New Mexico was quickly recognized as related to the Hantaan virus responsible for the outbreak of Korean epidemic hemorrhagic fever (EHF) among UN troops in 1951. Discovery of the new disease which was named the hantavirus pulmonary syndrome (HPS) and its causative agent the Sine Nombre virus (SNV) inspired detailed comparisons between the two disorders. Major damage to the epithelial cells of the capillaries and arterioles throughout the body leading to extensive capillary leak and subsequent hypotension and shock was the common denominator. The lung capillaries and arterioles were the focus of attack that could lead to rapid pulmonary failure in HPS and the corresponding renal and retroperitoneal vessels that caused a more protracted illness in EHF, but both displayed remarkably similar peripheral blood abnormalities including abnormal mononuclear cells, immature neutrophilia, thrombocytopenia, and hemoconcentration characteristic enough to make blood smear examination a useful tool in early diagnosis. There are evidences that a heavy virus presence in the involved endothelial cells is accompanied by various mononuclear cells capable of generating potent immune responses in these areas. Relevant toxic effects of systemically-administered high-dose interleukin-2 for resistant cancers include fever, chills, diarrhea, renal dysfunction, capillary leak syndrome accompanied by hypotension requiring aggressive pressor support, and occasional pleural effusions with diffuse pulmonary infiltrates and hypoxia severe enough to require ventilatory assistance. Peripheral blood mononuclear cells cultured in vitro with IL-2 secrete secondary cytokines such as IL-1, TNF-α, and interferon-gamma (IFN-γ). TNF-α, implicated in the pathophysiology of septic shock, is capable of inducing adult respiratory distress syndrome (ARDS) in experimental animals and humans. The strong similarity of these effects to the manifestations noted in the hantavirus diseases justifies the conviction that these and other cytokines involved in potent immune responses would constitute the pathogenic toxic substances predicted by perceptive early investigators of EHF. This concept is favored by clear indications that in both diseases active virus infection disappears the first few days and the ages of involvement correlate with periods of immunocompetence. The paradox of systemic injections of IL-2 that risk hantavirus-type toxicities for treating renal cell carcinoma and melanoma might be avoided by giving potentially more efficacious plant mitogens like PHA as previously reported. The expanded disclosure of a collaborator's method suggesting superior potential for cancer cure involves a unique application of pokeweed mitogen that delivers various cellular and cytokine responses directly to the tumor.

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