Indirect effects of oral tolerance improve wound healing in skin.

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.

Cell-mediated immune response to unrelated proteins and unspecific inflammation blocked by orally tolerated proteins.

Oral tolerance promotes a generalized decrease in specific immune responsiveness to proteins previously encountered via the oral route. In addition, parenteral immunization with a tolerated protein also triggers a significant reduction in the primary responsiveness to a second unrelated antigen. This is generally explained by 'innocent bystander suppression', suggesting that the transient and episodic effects of inhibitory cytokines released by contact with the tolerated antigen would block responses to the second antigen. In disagreement with this view, we have previously shown that: (i) these inhibitory effects do not require concomitance or contiguity of the injections of the two proteins; (ii) that intravenous or intragastric exposures to the tolerated antigen are not inhibitory; and (iii) that the inhibitory effect, once triggered, persists in the absence of further contact with the tolerated protein, possibly by inhibition of secondary responsiveness (immunological memory). The present work confirms that immunological memory of the second unrelated antigen is hindered by exposure to the tolerated antigen and, in addition, shows that this exposure: (i) inhibits the inflammation triggered by an unrelated antigen through the double effect of inhibiting production of leucocytes in the bone marrow and blocking their migration to inflammed sites; and (ii) significantly blocks footpaw swelling triggered by carrageenan. Taken together, these results conclusively demonstrate that inhibitory effects of parenteral injection of tolerated antigens are much more general than suggested by the 'innocent bystander suppression' hypothesis.