Current status and development prospects of aquatic vaccines

B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.

We normally live in symbiosis with approximately 10(13) bacteria present in the colon. Among the several mechanisms maintaining the bacteria/host balance, there is limited understanding of the structure, function, and properties of intestinal mucus. We now demonstrate that the mouse colonic mucus consists of two layers extending 150 mum above the epithelial cells. Proteomics revealed that both of these layers have similar protein composition, with the large gel-forming mucin Muc2 as the major structural component. The inner layer is densely packed, firmly attached to the epithelium, and devoid of bacteria. In contrast, the outer layer is movable, has an expanded volume due to proteolytic cleavages of the Muc2 mucin, and is colonized by bacteria. Muc2(-/-) mice have bacteria in direct contact with the epithelial cells and far down in the crypts, explaining the inflammation and cancer development observed in these animals. These findings show that the Muc2 mucin can build a mucus barrier that separates bacteria from the colon epithelia and suggest that defects in this mucus can cause colon inflammation.

The gut-associated lymphoid tissue is the largest immune organ in the body and is the primary route by which we are exposed to antigens. Tolerance induction is the default immune pathway in the gut, and the type of tolerance induced relates to the dose of antigen fed: anergy/deletion (high dose) or regulatory T-cell (Treg) induction (low dose). Conditioning of gut dendritic cells (DCs) by gut epithelial cells and the gut flora, which itself has a major influence on gut immunity, induces CD103(+) retinoic acid-dependent DC that induces Tregs. A number of Tregs are induced at mucosal surfaces. Th3 type Tregs are transforming growth factor-β dependent and express latency-associated peptide (LAP) on their surface and were discovered in the context of oral tolerance. Tr1 type Tregs (interleukin-10 dependent) are induced by nasal antigen and forkhead box protein 3(+) iTregs are induced by oral antigen and by oral administration of aryl hydrocarbon receptor ligands. Oral or nasal antigen ameliorates autoimmune and inflammatory diseases in animal models by inducing Tregs. Furthermore, anti-CD3 monoclonal antibody is active at mucosal surfaces and oral or nasal anti-CD3 monoclonal antibody induces LAP(+) Tregs that suppresses animal models (experimental autoimmune encephalitis, type 1 and type 2 diabetes, lupus, arthritis, atherosclerosis) and is being tested in humans. Although there is a large literature on treatment of animal models by mucosal tolerance and some positive results in humans, this approach has yet to be translated to the clinic. The successful translation will require defining responsive patient populations, validating biomarkers to measure immunologic effects, and using combination therapy and immune adjuvants to enhance Treg induction. A major avenue being investigated for the treatment of autoimmunity is the induction of Tregs and mucosal tolerance represents a non-toxic, physiologic approach to reach this goal. © 2011 John Wiley & Sons A/S.