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Title: ROLE FOR MIP-2, MIP-1 AND IL-1 IN DELAYED TYPE HYPERSENSITIVITY RESPONSE TO VIRAL ANTIGEN

Author
item Tumpey, Terrence
item FENTON, ROBIN - UNIV OF SO AL-MOBILE,AL
item MOLESWORTH-KENYON, SARA - UNIV OF SO AL-MOBILE,AL
item OAKES, JOHN - UNIV OF SO AL-MOBILE,AL
item LAUSCH, ROBERT - UNIV OF SO AL-MOBILE,AL

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/17/2002
Publication Date: 8/1/2002
Citation: N/A

Interpretive Summary: The development of an inflammatory response in viral sensitized hosts upon reexposure to viral antigen has been known for decades. However, the mechanism accounting for this immunologically specific response, termed delayed type hypersensitivity (DTH), is quite complex, and identification of the cellular and molecular events inherent in this phenomenon remains incomplete. A clearer understanding of the DTH mechanism is pertinent because it represents a form of cell-mediated immunity (CMI), and as such has the potential to provide protection against a virus. DTH can be elicited by inoculation of virus antigen into the skin of a virus infected mouse. The focus of the present investigation was to evaluate the contribution of neutrophils in the DTH response to viral antigen, and identify mediators which affect recruitment of these cells to the site of virus antigen deposition. We also investigated whether the recruited neutrophils helped to limit virus replication in immunized hosts.

Technical Abstract: Balb/c mice sensitized to HSV-1 develop a vigorous delayed type hypersensitivity (DTH) response upon intradermal virus antigen challenge. Although CD4+ T cells are a key mediator of this response, neutrophils are the most abundant cells at the antigen challenge site both initially and at the peak of the reaction. We investigated what role, if any, neutrophils play in DTH to a viral antigen. Here we show that antibody-mediated depletion of neutrophils one day before antigen challenge significantly suppressed ear swelling, and markedly reduced cellular influx. Additionally, neutrophil depletion was associated with decreased expression of MIP2, and MIP1 as well as with a 60-fold increase in HSV-1 replication. Neutralizing antibodies to neutrophil chemoattractants MIP2 or MIP1 but not KC significantly suppressed DTH and sharply reduced neutrophil accumulation in the ear pinna. Purified bone marrow-derived neutrophils exposed to IL1 produced chemokines in an 8 hr assay. Administration of neutralizing antibody to IL-1 significantly reduced ear swelling and suppressed the levels of MIP2, MIP1, MIP1, and RANTES. We conclude that neutrophils are a critical component of the DTH response to viral antigen. They are recruited to the DTH test site by MIP2 and MIP1 where they can be activated by IL1. The infiltrating cells also help suppress virus replication in immunized mice.