Orally induced peripheral nonresponsiveness is maintained in the absence of functional Th1 or Th2 cells

Intragastric administration of soluble protein Ags results in peripheral to lerance to the fed Ag, To examine the role of cytokine regulation in the in duction of oral tolerance, we fed OVA to mice deficient in Th1 (Stat 4(-/-) ) and Th2 (Stat 6(-/-)) cells and compared their response to that of normal BALB/c controls. We found that, in spite of these deficiencies, OVA-specif ic peripheral cell-mediated and humoral nonresponsiveness was maintained in both Stat 4(-/-) and Stat 6(-/-) mice, In the mucosa, both Peyer's patch T cell proliferative responses and OVA-specific fecal IgA were reduced in St at 4-/- and Stat 6(-/-) mice fed OVA but not in normal BALB/c controls. Muc osal, but not peripheral, nonresponsiveness was abrogated by the inclusion of a neutralizing Ab to TGF-beta in the culture medium. Our results show th at, in the periphery, tolerance to oral Ag can be induced in both a Th1- or Th2-deficient environment. In the mucosa, however, the absence of Th1 and Th2 cytokines can markedly affect this response, perhaps by regulation of T GF-beta-secreting cells.