Aspectos sistêmicos da tolerância oral

Abstract

Oral tolerance is traditionally understood as a reduction of specific immune responsiveness to ingested proteins due to lymphocyte activity decrease. Few attention has been given to systemic immunological activity in orally tolerant organisms. Paradoxically, we found that specific lymphocyte activity inhibition was parallel to an increased global lymphocyte activity. C57BL/6 mice rendered orally tolerant to ovalbumin showed the characteristic suppression of antigen specific antibody responses in all serum immunoglobulin classes analyzed: IgG1, IgE, IgM and IgA. Nevertheless, these mice presented total IgA levels similar to immunized mice and higher levels of total IgM in serum. Accordingly, orally tolerant mice had higher number of immunoglobulin secreting cells (ISC) in spleen and bone marrow. Moreover, tolerant mice Ig-secreting cells in spleen were mainly IgM and IgA producers, whereas immunized mice had mostly IgG-secreting cells. Despite having the same number of regulatory and activated T cells in spleen after booster immunization, tolerant animals exhibit a different cells appearance kinetics in the spleen after the primary intraperitoneal immunization with antigen and adjuvant. Tolerant mice showed an earlier expansion of CD4+CD44high effector/memory T cell as soon as one day after immunization while immunized mice had these cells expanded at the fourth day. Similarly, CD4+Foxp3+ regulatory T cells appeared sooner in tolerant mice, two days after immunization. Immunized mice showed a CD4+Foxp3+ Treg cells expansion delay, achieving higher cells frequencies and numbers 7 days after immunization. Importantly, orally tolerant mice presented higher numbers of CD4+CD69+ T cells and CD4+CD25+LAP+ regulatory T cells in spleen even before parenteral immunization. Also, at this time tolerant animals showed a higher expression of regulatory cytokines (TGF- and IL-10) and a transient expression of lymphocyte activation cytokines (IL-2 and IFN-). Thus, over inhibiting specific responsiveness, orally-tolerant mice display an early and widespread mobilization of activated and regulatory lymphocytes.