The administration of IL-2 leads to lymphocyte activation in vivo as well as the release of several secondary cytokines resulting in tumor regression in approximately one-third of patients with either renal cell carcinoma or malignant melanoma. This form of immunotherapy is associated with severe side effects, some of which are presumably mediated by tumor necrosis factor, IL-1, and other pyrogenic cytokines generated in response to IL-2. Indeed, the infusion of these cytokines is known to induce fever, hypotension, and an acute respiratory distress syndrome (ARDS) in recipient animals, all of which strongly resemble the hemodynamic and metabolic alterations observed in cancer patients treated with IL-2. In addition, several lines of evidence suggest that the endothelium may be directly injured by IL-2-activated CD16+ lymphocytes (NK cells), resulting in a diffuse increase in vascular permeability (capillary leak syndrome). Finally, high levels of activated complement components, some of which are known to function as potent anaphylatoxins, have been detected in the plasma of patients undergoing immunotherapy with IL-2. This renewal grant application will systematically evaluate leukocyte-endothelial interactions as they relate to endothelial injury and the induction of capillary leak. The mechanism by which complement is activated in patients undergoing immunotherapy with IL-2 will be explored in depth. The proposal contains several studies focused on the evaluation of agents known to antagonize the activation of neutrophils by TNF, one of the cytokines present in the serum of patients receiving IL-2. Other studies will evaluate agents that inhibit the release of TNF and other cytokines capable of causing capillary leak in experimental animals. Since the capillary leak syndrome has also been observed in patients receiving TNF alpha and in those undergoing treatment with high-dose GM-CSF, this investigation will provide information relevant to the clinical use of biological response modifiers in addition to IL-2. These proposed studies will not only clarify the mechanism of increased vascular permeability associated with IL-2 therapy, but will address several fundamental aspects of leukocyte-endothelial cell interactions, lymphokine networks, and complement activation, which may be relevant to cytokine-induced tumor regression as well as toxicity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043950-05
Application #
3186452
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1990-02-01
Project End
1995-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Vannier, E; Kaser, A; Atkins, M B et al. (1999) Elevated circulating levels of soluble interleukin-1 receptor type II during interleukin-2 immunotherapy. Eur Cytokine Netw 10:37-42
Tilg, H; Dinarello, C A; Mier, J W (1997) IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. Immunol Today 18:428-32
Stoddart Jr, J H; Jasuja, R R; Sikorski, M A et al. (1996) Protease-resistant L-selectin mutants. Down-modulation by cross-linking but not cellular activation. J Immunol 157:5653-9
Sikorski, M A; Staunton, D E; Mier, J W (1996) L-selectin crosslinking induces integrin-dependent adhesion: evidence for a signaling pathway involving PTK but not PKC. Cell Adhes Commun 4:355-67
Tilg, H; Atkins, M B; Dinarello, C A et al. (1995) Induction of circulating interleukin 10 by interleukin 1 and interleukin 2, but not interleukin 6 immunotherapy. Cytokine 7:734-9
Tilg, H; Shapiro, L; Vannier, E et al. (1994) Induction of circulating antagonists to IL-1 and TNF by IL-2 administration and their effects on IL-2 induced cytokine production in vitro. J Immunol 152:3189-98
Tilg, H; Trehu, E; Atkins, M B et al. (1994) Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83:113-8
Tilg, H; Trehu, E; Shapiro, L et al. (1994) Induction of circulating soluble tumour necrosis factor receptor and interleukin 1 receptor antagonist following interleukin 1 alpha infusion in humans. Cytokine 6:215-9
Trehu, E G; Isner, J M; Mier, J W et al. (1993) Possible myocardial toxicity associated with interleukin-4 therapy. J Immunother Emphasis Tumor Immunol 14:348-51
Tilg, H; Pape, D; Trehu, E et al. (1993) A method for the detection of erythrocyte-bound interleukin-8 in humans during interleukin-1 immunotherapy. J Immunol Methods 163:253-8

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