In this study, we examined the effects of murine chemokine DNA, as genetic adjuvants given mucosally, on the systemic and distal mucosal immune responses to plasmid DNA encoding gB of herpes simplex virus (HSV) by using the mouse model. The CC chemokines macrophage inflammatory protein 1␤ (MIP-1␤) and monocyte chemotactic protein 1 (MCP-1) biased the immunity to the Th2-type pattern as judged by the ratio of immunoglobulin isotypes and interleukin-4 cytokine levels produced by CD4 ؉ T cells. The CXC chemokine MIP-2 and the CC chemokine MIP-1␣, however, mounted immune responses of the Th1-type pattern, and such a response rendered recipients more resistant to HSV vaginal infection. In addition, MIP-1␣ appeared to act via the upregulation of antigen-presenting cell (APC) function and the expression of costimulatory molecules (B7-1 and B7-2), whereas MIP-2 enhanced Th1-type CD4 ؉ T-cell-mediated adaptive immunity by increasing gamma interferon secretion from activated NK cells. Our results emphasize the value of using the mucosal route to administer DNA modulators such as chemokines that function as adjuvants by regulating the activity of innate immunity. Our findings provide new insight into the value of CXC and CC chemokines, which act on different innate cellular components as the linkage signals between innate and adaptive immunity in mucosal DNA vaccination.Mucosal surfaces represent the primary site for the transmission of several viruses including human immunodeficiency virus and herpes simplex virus (HSV). In consequence, immunity at mucosal sites represents an important issue in vaccine development. Mucosae have numerous innate defenses, some of which serve to alert and direct the nature of subsequent acquired immune events (1, 10). Interest has recently focused on cytokines and chemokines and the role they appear to play as modulators of the adaptive immune responses (12, 31). Accordingly, members of both types of molecules induced nonspecifically upon infection are involved in regulating the inflammatory reaction and the subsequent adaptive Th1 or Th2 type of T-cell reaction that occurs in the draining lymphoid tissue. Consequently, manipulating the expression of cytokines and chemokines during exposure to infectious agents or vaccine represents a valuable approach to achieve optimal protection.Most information on immunomodulatory effects of immune mediators has emphasized cytokines (34, 40). However, various chemokines may represent even more useful innate modulators since these molecules are involved in the recruitment and activation of cells related to innate immunity (35, 39). Currently, little is known about the nonspecific adjuvant effect of chemokines, and the two previous studies which used chemokine DNA given systemically with antigen (Ag) provided conflicting data (13,18). In the present study, we investigated whether genetic cotransfer of certain chemokines along with plasmid DNA encoding viral Ag to a mucosal site can affect the efficiency of subsequent acquired mucosal and systemic immune re...

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This study evaluates the role of antibody as an indicator of immunity to ocular challenge with herpes simplex virus (HSV). Two genotypes of mice, BALB/c or BALB/c with mu-chain knockout (muK/O; which lack functional B cells), were immunized systemically either with nonvirulent infectious virus or with a eukaryotic expression plasmid encoding glycoprotein B (gB). Whereas naive muK/O mice were 10- to 100-fold more susceptible to HSV infection than BALB/c mice, following immunization both groups showed similar levels of resistance to ocular challenge. Thus both HSV-immunized groups cleared virus within 3 days and showed no signs of ocular lesions. gB DNA-immunized mice cleared virus less rapidly (5 days), and the incidence of lesions was 10 and 25% in BALB/c and muK/O mice, respectively. Since muK/O mice failed to produce detectable anti-HSV antibody, the mechanism of rapid viral removal was assumed to have a T cell basis. However, T cells would likely not mediate any protection directly since such cells were absent in infected corneas during clearance. A likely mechanism of immunity could involve innate defenses, perhaps enhanced by the action of cytokines released from antigen-reactive CD4+ cells in vascularized tissue adjacent to the cornea. Thus an abrupt inflammatory response consisting principally of neutrophils occurred in the corneal stroma in immune mice, and this subsided when virus disappeared. These data reveal that even though the deficiency in generating antibody renders mice more susceptible to HSV infection, once primed, resistance to disease expression is mediated solely by the cellular components and their products.