Interleukin 1-induced pathophysiology: induction of cytokines, development of histopathologic changes, and immunopharmacologic intervention.

In this report, we describe a murine system in which treatment with recombinant human interleukin 1 (IL-1) induced an acute lethal state with pathologic changes similar to septic shock at high doses and development of arthritic and other tissue changes following more prolonged treatment with lower doses. We have demonstrated that both recombinant human interleukin 1 alpha and recombinant human interleukin 1 beta could be administered to an endotoxin hyporesponsive strain, C3H/HeJ, and produce these pathologic changes. Induction of tumor necrosis factor (TNF) and colony-stimulating factor activity was noted. The ability to induce these changes was dose and time dependent. Histopathologic changes included lesions in the lung, heart, liver, adrenal glands, intestines, and joints. Neutrophil infiltration was a prominent feature in many organs. Drugs, immunotherapy, or other treatments which have been effective in delaying or preventing a lethal syndrome induced following high dose interleukin 2 therapy were not effective in preventing the interleukin 1-induced lethal syndrome. Interestingly, pretreatment with low nonlethal doses of IL-1 (but not lipopolysaccharides or TNF) could prevent deaths from an LD100 challenge dose of IL-1.

Neuroendocrine regulation of in vivo cytokine production and effects: I. In vivo regulatory networks involving the neuroendocrine system, interleukin-1 and tumor necrosis factor-alpha.

We have investigated the in vivo regulatory network involving the neuroendocrine system, interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF). Adrenalectomy or hypophysectomy shifted the sensitivity curve to lipopolysaccharide (LPS)-induced lethal shock as well as TNF- and IL-1-induced deaths. Serum levels of IL-1 or TNF were altered in adrenalectomized or hypophysectomized mice following in vivo stimulation with LPS when compared to appropriate sham-operated control mice. Exogenous administration of either IL-1 or TNF could induce increases in serum corticosterone in sham-operated mice. Finally, treatment of adrenalectomized mice with corticosterone or dexamethasone could inhibit the induction of serum IL-1 and TNF and modified the pattern of these cytokine-induced deaths. Dexamethasone was more effective in these conditions than the natural glucocorticoid, corticosterone. Taken together, these data provide in vivo evidence for a feedback system involving the neuroendocrine axis (hypothalamus, pituitary and adrenal glands) leading to corticosterone production and subsequent regulation and/or modulation of IL-1 or TNF levels or activity.

Interleukin-2 induced systemic toxicity: induction of mediators and immunopharmacologic intervention.

Interleukin-2 has been tested as an anti-cancer agent, either alone or in combination with immune cells, but severe dose limiting adverse toxic effects have been observed. Because the pathogenesis of the toxicity has remained uncharacterized, it has not been possible to determine whether the therapeutic and the toxic events could be separated. We have examined immunopharmacologic regulation of IL2 induced mediator induction and toxicity syndrome and have compared this data with our earlier information on IL2 enhancement of immune function in murine systems. The results of this study have shown that treatment with recombinant human interleukin-2 induced increased cellular TNF activity in lymphoid organs and this activity was abrogated by an anti-TNF antibody. Additionally, continuous daily treatment with interleukin-2 also induced increases in serum corticosterone but no detectable increases in serum IL1 or TNF. The increases in serum corticosterone occurred later in the treatment process and coincided with histopathologic changes in the adrenal glands and other tissues. Animals that died as a result of IL2 treatment had ascites and hydrothorax. Histopathologic changes were noted in the lungs, liver, adrenals, kidneys, gastrointestinal tract, heart and lymphoid organs. Cyclophosphamide, dexamethasone and anti-ASGM1 antibody were most effective in increasing survival and inhibiting immune enhancement but differentially effective in inhibiting TNF induction (or in certain cases gamma interferon induction), decreasing ascites or hydrothorax or affecting lymphoid proliferation in the lungs and spleen. Cyclosporin A and azathioprine were not as effective in enhancing survival and had differential effects on the other parameters. Possible mechanisms of both therapeutic and toxic events are discussed.

The progression of the inflammation in established collagen-induced arthritis can be altered by treatments with immunological or pharmacological agents which inhibit T cell activities.

Alterations in the progression of the inflammatory disease in mice with established collagen-induced arthritis (CIA) by in vivo treatments with either anti-T cell antibodies or an immunosuppressive drug, whose main targets of action are T cells, were studied. It was demonstrated that the in vivo administration of either monoclonal anti-L3T4, anti-Ly-2 or the combination of anti-L3T4 and anti-Ly-2 failed to modify the inflammatory disease after the arthritis had been initiated. Nevertheless, the progression of disease was decreased by treatments with rabbit anti-mouse lymphocyte sera (ALS) in mice with established CIA. While there was a substantial reduction in the proliferative responses to the T cell mitogen concanavalin A (Con A) in these ALS-treated mice, proliferation to a B cell mitogen, lipopolysaccharide, was unaffected. Furthermore, treatments with anti-Thy-1.2 monoclonal antibody (mAb) by itself did not alter the progression of the ongoing inflammatory disease, but combined treatments with both anti-Thy-1.2 and anti-L3T4 mAb prevented the further advancement of the arthritic disease. Although mice receiving either anti-Thy-1.2 alone or both anti-Thy-1.2 and anti-L3T4 exhibited complete absence of Thy-1+ cells within their inguinal lymph nodes, the proliferative responses to Con A by LN cells from mice treated with the combination of anti-Thy-1.2 and anti-L3T4 were drastically reduced compared to the responses of either the anti-Thy-1.2 or anti-L3T4-treated groups. Finally, daily treatments with cyclosporin A, an immunosuppressive drug which preferentially acts on T cells, were also effective in modifying the clinical course of the arthritic disease in mice with established CIA. These results suggest that immunocompetent cells which express the Thy-1 surface marker, most likely Thy-1+ T cells, may play a role in maintaining and perpetuating the inflammatory disease of established CIA.