fetal development or birth may result in establishment of central tolerance, as was observed in medawar's mouse-allograft experiments. in usual transplant cases, however, such early prior exposure is not possible. nonetheless, a few patients can still develop allograft tolerance upon cessation of all exogenous immunosuppressive therapy, a condition referred to as operational tolerance. cd4+ foxp3+ treg cells, as well as cd8+ cd28- regulatory t cells that dampen cytotoxic responses to grafted organs, are thought to play a role. in addition, genes involved in nk cell and γδt cell function associated with tolerance have been implicated for liver transplant patients. the unique gene signatures of these patients implies their physiology may be predisposed toward immune tolerance. fetal development main article: immune tolerance in pregnancy the fetus has a different genetic makeup than the mother, as it also translates its father's genes, and is thus perceived as foreign by the maternal immune system. women who have borne multiple children by the same father typically have antibodies against the father's red blood cell and major histocompatibility complex (mhc) proteins. however, the fetus usually is not rejected by the mother, making it essentially a physiologically tolerated allograft. it is thought that the placental tissues which interface with maternal tissues not only try to escape immunological recognition by downregulating identifying mhc proteins but also actively induce a marked peripheral tolerance. placental trophoblast cells express a unique human leukocyte antigen (hla-g) that inhibits attack by maternal nk cells. these cells also express ido, which represses maternal t cell responses by amino acid starvation. maternal t cells specific for paternal antigens are also suppressed by tolerogenic dcs and activated itregs or cross-reacting ntregs. some maternal treg cells also release soluble fibrinogen-like proteins 2 (sfgl2), which suppresses the function of dcs and macrophages involved in inflammation and antigen presentation to reactive t cells these mechanisms altogether establish an immune-privileged state in the placenta that protects the fetus. a break in this peripheral tolerance results in miscarriage and fetal loss. (for more information, see immune tolerance in pregnancy). the microbiome the skin and digestive tract of humans and many other organisms is colonized with an ecosystem of microorganisms that is referred to as the microbiome. though in mammals a number of defenses exist to keep the microbiota at a safe distance, including a constant sampling and presentation of microbial antigens by local dcs, most organisms do not react against commensal microorganisms and tolerate their presence. reactions are mounted, however, to pathogenic microbes and microbes that breach physiological barriers(epithelium barriers). peripheral mucosal immune tolerance, in particular, mediated by itreg cells and tolerogenic antigen-presenting cells, is thought to be responsible for this phenomenon. in particular, specialized gut cd103+ dcs that produce both tgf-β and retinoic acid efficiently promotes the differentiation of itreg cells in the gut lymphoid tissue. foxp3- tr1 cells that make il-10 are also enriched in the intestinal lining. break in this tolerance is thought to underlie the pathogenesis of inflammatory bowel diseases like crohn's disease and ulcerative colitis. oral tolerance and hypersensitivity