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American Journal of Pathology, Vol 143, 1179-1188, Copyright © 1993 by American Society for Investigative Pathology

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The production of chemotactic cytokines in an allogeneic response. The role of intercellular adhesion molecule-1 and lymphocyte function- associated antigen-3

NW Lukacs, SL Kunkel, MD Burdick and RM Strieter
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0360.

The in vitro mixed lymphocyte reaction (MLR) is regarded as a model of responsiveness to allogeneic major histocompatibility complex antigens and has historically been used to elucidate the pathway of T lymphocyte proliferation. In addition, the MLR response may reflect activation pathways relevant in acute allograft rejection. In the present study, we have applied the MLR to examine the role of adhesion molecules intercellular adhesion molecule-1 and lymphocyte function-associated antigen-3 in the induction of tumor necrosis factor-alpha (TNF-alpha) as well as chemotactic cytokines, interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha). Monoclonal antibodies to the adhesion molecules (5 micrograms/ml) were added to one-way human MLR cultures and supernatants collected at various time points. The monoclonal antibodies to the adhesion molecules significantly suppressed the proliferative response by 50 to 80%. Cytokine production, TNF-alpha (3.2 +/- 0.5 ng/ml), MIP-1 alpha (12.9 +/- 3.3 ng/ml), MCP-1 (18.8 +/- 3.4 ng/ml), and IL-8 (57 +/- 18 ng/ml) peaked on day 5 of the assay. The addition of anti-intercellular adhesion molecule-1 to the cultures suppressed TNF-alpha, MIP-1 alpha, MCP-1, and IL-8 production by 68% (1.05 +/- 0.29 ng/ml), 85% (2.0 +/- 1.2 ng/ml), 63% (6.8 +/- 2.9 ng/ml), and 47% (30.3 +/- 3.7 ng/ml), respectively. Likewise, the addition of anti-lymphocyte function-associated antigen-3 monoclonal antibody suppressed the cytokines by 78% (0.71 +/- 0.34 ng/ml), 66% (4.5 +/- 2.2 ng/ml), 52% (8.8 +/- 2.2 ng/ml), and 73% (15.7 +/- 4.4 ng/ml), respectively. Immunohistochemical staining indicated that monocytes were the primary source of the chemokines IL-8, MCP-1, and MIP-1 alpha. The addition of exogenous recombinant TNF-alpha (5 ng/ml) or recombinant IL-2 (5 units/ml) to the anti-intercellular adhesion molecule-1-treated cultures allowed the recovery of the proliferative response as well as restoration of IL-2, TNF-alpha, and IL-8, but not MCP-1 or MIP-1 alpha, indicating that both soluble and adhesion molecule signals are required for the production of the C-C family of chemokines in allogeneic responses. Thus, the events resulting in cellular proliferation and chemokine production were dependent on adhesion molecule interactions.

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