Modulation of systemic antigen‐specific immune responses by oral antigen in humans

Abstract

Oral antigen uptake can induce systemic immune responses ranging from tolerance to immunity. However, the underlying mechanisms are poorly understood, especially in humans. Here, keyhole limpet hemocyanin (KLH), a neoantigen which has been used in earlier studies of oral tolerance, was fed in a repeated low-dose and a single high-dose protocol to healthy volunteers. KLH-specific CD4 1 T-cell proliferation and cytokine production, as well as KLH-specific serum Ab and the effects of oral KLH on a subsequent parenterally induced systemic immune response, were analyzed. Repeated low-dose oral KLH alone induced antigen-specific CD4 1 T cells positive predominantly for the gut-homing receptor integrin b7 and the cytokines IL-2 and TNF-a; some CD4 1 T cells also produced IL-4.Oral feeding of KLH accelerated a subsequent parenterally induced systemic CD4 1 T-cell response. The cytokine pattern of KLH-specific CD4 1 T cells shifted toward more IL-4-and IL-10-and less IFN-c-, IL-2-and TNF-a-producing cells. The parenterally induced systemic KLH-specific B-cell response was accelerated and amplified by oral KLH. The impact of single high-dose oral KLH on antigen-specific immune responses was less pronounced compared with repeated low-dose oral KLH. These findings suggest that oral antigen can effectively modulate subsequently induced systemic antigen-specific immune responses. Immunomodulation by oral antigen may offer new therapeutic strategies for Th type1-mediated inflammatory diseases and for the development of vaccination strategies. [1,[4][5][6][7]. Systemic tolerance in these models may result from a variety of effects including clonal anergy, clonal deletion and active regulation [2]. Understanding the mechanisms leading to such diverse outcomes after mucosal antigen uptake is not only important for mucosal vaccination [3,7], but may also offer new options for immunomodulation or the treatment of autoimmune diseases [8][9][10]. Unfortunately, responses to oral antigen differ significantly between species [8,11], and human studies are rare.Similar to mouse models, systemic immune responses can be induced in humans by oral uptake of pathogens which invade the mucosa, e.g. Salmonella typhi Ty21a [12,13], or of toxins which can bind to mucosal epithelial cells and compromise the mucosal barrier, e.g. cholera toxin [14,15].The induction of human oral tolerance has been described [16][17][18] after feeding keyhole limpet hemocyanin (KLH), a neoantigen which is safe to use in humans. Compared with rodent studies, the antigen doses used were much lower and effects observed were not as uniform: reduced delayed-type hypersensitivity (DTH) [17,18] and antigen-specific proliferation of PBMC [16][17][18] have been reported after feeding KLH, although KLH-specific B-cell responses were unaffected [16] or even amplified [17,18].Functional Th-cell subsets are believed to determine the type of immune responses, but have not been examined after oral antigen challenge in humans. The frequencies of human antigenspecific Th cells or e...

Oral tolerance induction in humans

“…These differences might be due to the lower amount of KLH fed in this study (Kapp et al, No effect n.d Within CD4 + IL-4: no effect IL-10: no effect Within CD4+ IFN-γ: ↓ IL-2: no effect TNF-α: no effect Within CD4+ CLA: ↓ α4β7 j : no effect Kapp et al (2010) Within CD4+CD154 + IL-4: no effect IL-10: no effect Within CD4+CD154 + IFN-γ: no effect IL-2: no effect TNF-α: no effect Within CD4+CD154 + CLA: ↓ α4β7: no effect IgA: no effect IgG: no effect IgM: no effect IL-4: no effect IL-10: (↑) TGF-β: no effect IFN-γ: no effect IL-2 : no effect 2010). Kapp et al administered KLH in acid-resistant capsules and investigated two dosage modes: one group ingested 5 mg of KLH for 10 days ("repeated low dose"), and another group 50 mg of KLH at one day ("single high dose") i.e.…”

“…However, only three individuals (two of the control group and one of the oral group) were analyzed for CLA expression. A decline of CLA expression after orally priming was previously also seen in KLH-specific CD4+ T cells (Kapp et al, 2010).…”

Mechanisms of Oral Tolerance to Soluble Protein Antigens

“…Analysis identified positive results in the collagen type I treated group with late phase DCSSC, which may identify a group for future studies. In a nondisease study, feeding normal subjects high or low doses of keyhole limpet hemocyanin (KLH) followed by immunization modulated systemic KLH-specific immune responses (Kapp et al, 2010).…”

Response to Cutaneous Immunization with Low-Molecular-Weight Subunit Keyhole Limpet Hemocyanin

“…In a recent study, low-dose oral KLH induced an antigen-specific systemic CD4+ T cell response with a shift toward a Th2 cytokine pattern. Later parenteral immunization boosted B cell responses and shifted the cytokine pattern of KLH-specific CD4+ T cells from a Th1 towards a Th2 pattern, suggesting a novel effect of oral immunomodulation [20]. …”