Tissue injury in adult mammalian skin frequently results in scarring while fetal mammalian skin heals with complete regeneration. Inflammatory reactions are among the factors thought to impair regeneration. Previous studies have shown that the injection of an immunologically tolerated protein blocks immune responses to unrelated antigens and is also able to inhibit inflammation in mice. This phenomenon, which we refer to as the indirect effects of oral tolerance, does not require the simultaneous injection of the tolerated antigen and the second antigen, and also occurs when the two antigens are given by separate routes of immunization. Herein, we investigated whether the i.p. injection of an orally tolerated antigen (ovalbumin, OVA) would inhibit inflammatory reactions at an incisional lesion and influence healing of adult mouse skin. In OVA-tolerant mice, the injection of OVA minutes before wounding altered inflammation: it reduced the numbers of mast cells, neutrophils, and lymphocytes but increased the number of macrophages around the lesion area. Tolerant mice also showed fewer myofibroblasts and reduced scar area. Furthermore, tolerant mice displayed a pattern of extracellular matrix deposition similar to that observed in intact skin, plus characteristics of regeneration, such as an increased deposition of fibronectin and tenascin-C. These observations suggest that the indirect effects of oral tolerance can alter the process of wound healing in skin and reduce scar formation.

Oral tolerance is a phenomenon that may occur in animals exposed to soluble antigens for the first time by the oral route. In the present study, we show that oral tolerance against ovalbumin (Ova) can be obtained after intragastric administration of the antigen in the presence of free residues of palmitate. On the other hand, oral tolerance induction is blocked when the residues of palmitate are covalently bound to the antigen (Ova-palmitate conjugates). We have also noticed that oral administration of Ova-palmitate conjugates can boost and/or prime experimental animals for Ova-specific cellular and humoral systemic immune responses. Oral treatment with the conjugates also induces the production of local secretory immunoglobulin A (IgA) as measured in intestinal washes. Furthermore, Ova-palmitate given orally can inhibit oral tolerance induction by naõÈ ve Ova.

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Previous work in this laboratory has demonstrated that ovalbumin coupled to palmitoyl residues (palmitoyl‐Ova) does not induce oral tolerance. The present study sought to determine whether this coupling affects digestion, absorption and transfer of antigen. Ova and palmitoyl‐Ova were shown to be digested differently in vitro by proteolytic enzymes and presented different tissue distribution kinetics after being labelled with 99mtechnetium and orally administered to animals. Palmitoyl‐Ova remained longer in the stomach, while native Ova was quickly transferred to the gut and other organs. After 3 h, higher levels of palmitoyl‐Ova were found in the blood, Peyer's patches, mesenteric lymph nodes, liver and, especially, the spleen, which appears to be essential for immunization with palmitoyl‐Ova. In fact, splenectomized mice treated orally with palmitoyl‐Ova became tolerant, while tolerance to Ova was not affected. Thus, palmitoyl coupling was demonstrated to affect antigen digestion, absorption and transport. This is the first time that the spleen has been shown to be required for oral immunization with palmitoyl‐Ova.

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