Therapeutic manipulation of the immune system: enhancement of innate and adaptive mucosal immunity.

Abstract

The mucosal immune system has evolved alongside, but separate, from the general systemic immune system. As a major consequence of this dichotomy, only immune responses initiated in mucosal inductive sites can result in effective immunity in mucosal tissues themselves. Oral tolerance, as usually assessed as orally-induced systemic unresponsiveness, contributes to mucosal homoeostasis by preventing unwanted immune reactions to food or environmental antigens. It is now established that tolerance can also be induced by the nasal route and mucosally-induced tolerance is being actively investigated for immune therapy against a number of diseases. Nontoxic derivatives of cholera toxin and the heat labile toxin of Escherichia coli as well as chimeric enterotoxins have been developed. These molecules retain the mucosal adjuvant activity of native enterotoxins and are effective at inducing targeted Th1 or Th2- type immune responses. Mucosal delivery of cytokines as adjuvants represents a safer alternative to parenteral cytokine injection. Nasally administered cytokines such as IL-1 and IL-12 or chemokines including RANTES, lymphotactin, MIP-1 beta, all act as mucosal adjuvants for co-administered antigens. Each of these cytokines promote specific pattern of CD4(+) T helper cell cytokine responses that could be exploited for targeted immune therapy. Although GALT and NALT are both parts of the Common Mucosal Immune System, there are major differences between orally and nasally induced immune responses. Nasal vaccines more effectively promote protective immunity in the genitourinary tract than do oral vaccines. In addition, aging affects mucosal tolerance or immunity in GALT more than is seen in NALT. Therapeutic manipulation of mucosal immunity involves regulation of CD4(+) T cell cytokine responses and thus, should require a careful examination of the host status, including the occurrence of inflammatory bowel diseases.