Modulation of immune responses using adjuvants to facilitate therapeutic vaccination.

Therapeutic vaccination offers great promise as an intervention for a diversity of infectious and non-infectious conditions. Given that most chronic health conditions are thought to have an immune component, vaccination can at least in principle be proposed as a therapeutic strategy. Understanding the nature of protective immunity is of vital importance, and the progress made in recent years in defining the nature of pathological and protective immunity for a range of diseases has provided an impetus to devise strategies to promote such responses in a targeted manner. However, in many cases, limited progress has been made in clinical adoption of such approaches. This in part results from a lack of safe and effective vaccine adjuvants that can be used to promote protective immunity and/or reduce deleterious immune responses. Although somewhat simplistic, it is possible to divide therapeutic vaccine approaches into those targeting conditions where antibody responses can mediate protection and those where the principal focus is the promotion of effector and memory cellular immunity or the reduction of damaging cellular immune responses as in the case of autoimmune diseases. Clearly, in all cases of antigen-specific immunotherapy, the identification of protective antigens is a vital first step. There are many challenges to developing therapeutic vaccines beyond those associated with prophylactic diseases including the ongoing immune responses in patients, patient heterogeneity, and diversity in the type and stage of disease. If reproducible biomarkers can be defined, these could allow earlier diagnosis and intervention and likely increase therapeutic vaccine efficacy. Current immunomodulatory approaches related to adoptive cell transfers or passive antibody therapy are showing great promise, but these are outside the scope of this review which will focus on the potential for adjuvanted therapeutic active vaccination strategies.

Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-gamma.

Previous studies have suggested that intestinal epithelial cells (IECs) have the capacity to function as nonprofessional antigen presenting cells that in the normal state preferentially activate CD8+ T cells. However, under pathological conditions, such as those found in inflammatory bowel disease (IBD), persistent activation of CD4+ T cells is seen. The aim of this study was to determine whether the IBD IECs contribute to CD4+ T cell activation. Freshly isolated human IECs were obtained from surgical specimens of patients with or without IBD and cocultured with autologous or allogeneic peripheral blood T lymphocytes. Cocultures of normal T cells and IECs derived from IBD patients resulted in the preferential activation of CD4+ T cell proliferation that was associated with significant IFN-gamma, but not IL-2, secretion. Cytokine secretion and CD4+ T cell proliferation was inhibited by pretreatment of the IBD IECs with the anti-DR MAb L243. In contrast, normal IECs stimulated the proliferation and cytokine secretion by CD4+ T cells to a significantly lesser degree than IBD IECs. Furthermore, blockade of human leukocyte antigen-DR had a lesser effect in the normal IEC-CD4+ T cell cocultures. We conclude that IECs can contribute to the ongoing CD4+ T cell activation seen in IBD. We suggest that the apparent differences between the secreted levels of IFN-gamma indicate that it may play a dual role in intestinal homeostasis, in which low levels contribute to physiological inflammation whereas higher levels are associated with an uncontrolled inflammatory state.

The expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells.

BACKGROUND & AIMS: Previous studies have suggested that intestinal epithelial cells (IECs) may function as antigen-presenting cells for CD4+ and CD8+ T cells. However, these cells fail to express conventional costimulatory molecules (CD80, CD86), leading to the possibility that antigen presented by normal IECs could result in anergy. Other members of the B7 family have recently been identified. B7h interacts with inducible costimulator (ICOS) on T cells and provides a positive signal, whereas B7-H1 and B7-DC interact with PD-1 and transmit an inhibitory signal. Our aim was to determine whether IECs express novel B7 family members and whether these molecules play a role in IEC:T-cell interactions. METHODS: B7h and B7-H1 expression was assessed in isolated IECs and IEC lines. The functional role of B7h and B7-H1 in the interaction between IECs and T cells was assessed in coculture experiments using purified anti-B7h or B7-H1 monoclonal antibodies (mAbs), B7h immunoglobulin (Ig), or B7-H1 fusion proteins. RESULTS: B7h and B7-H1 messenger RNA was detected in IEC lines and IECs from healthy controls and patients with inflammatory bowel disease (IBD). IECs from patients with IBD but not healthy controls expressed B7h and B7-H1 protein on their surface. Proliferation of IEC-stimulated T cells was inhibited only by B7h immunoglobulin treatment, whereas interferon gamma secretion in these cocultures was inhibited by both anti-B7h mAb and B7h Ig. No difference was seen between IBD or normal IEC populations. CONCLUSIONS: These data suggest that the B7h-ICOS costimulatory pathway may be important in IEC:T-cell interactions.