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

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⁺ 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⁺ T cells positive predominantly for the gut‐homing receptor integrin β7 and the cytokines IL‐2 and TNF‐α; some CD4⁺ T cells also produced IL‐4. Oral feeding of KLH accelerated a subsequent parenterally induced systemic CD4⁺ T‐cell response. The cytokine pattern of KLH‐specific CD4⁺ T cells shifted toward more IL‐4‐ and IL‐10‐ and less IFN‐γ‐, IL‐2‐ and TNF‐α‐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.