Induction of thymic tolerance as possibility in prevention of recurrent spontaneous abortion

Abstract

Summary A major process through which the immune system becomes tolerant to self-proteins involves the deletion of self-reactive cells in the thymus and/or inhibition of specific Th 1 cells clones. Deletion process includes two selection mechanisms in which the thymus eliminates unwanted thymocytes are known as positive selection and negative selection. The thymus is an antigenically privileged site, mainly for it is discrete by blood-thymus barrier. Many researches were shown that intrathymic inoculation of any antigen resulted in specific tolerance induction. The embryo/fetus and placenta are an allograft to which the mother must remain immunologically tolerant in order for the fetus to survive. Today, there is much interest focused on the immunology of recurrent spontaneous abortion (RSA). Up to 50% of RSA may be mediated by the immune system via inadequate maternal anti-paternal response. Nature of this maternal-fetal disturbance represents disbalance in Th 1 =Th 2 activity. Contra-shift in Th 1 =Th 2 activity is the basis for immunotherapy with paternal leukocyte immunization (PLI). PLI induce some kind of peripheral tolerance on embryonic/fetal/trophoblast antigens, but problems of central tolerance are still open. Intrathymic inoculation of fetal or paternal cells (like leukocyte, thymic dendritic cells, trophoblast cells) or paternal set of MHC molecules may cause central specific tolerance and may be a new possibility for immunotherapy in RSA patients. ª

Dysregulation of CD4+CD25+CD127lowFOXP3+ regulatory T cells in HIV-infected pregnant women

“…1 The association between HY-restricting human leukocyte antigen (HLA) class II alleles and recurrent miscarriage subsequent to a firstborn boy indicates a CD4 ϩ T cell-mediated mechanism in these cases. 2 How the fetus normally evades a maternal immune response is not fully known, but development of fetal-maternal tolerance possibly relies on alterations of both central (thymic) tolerance [3][4][5][6] and peripheral tolerance mediated by regulatory T cells (Tregs). [7][8][9][10][11] The thymus is reduced in size and changed in structure during pregnancy, and in mice a substantial loss of thymocyte proliferation occurs from early pregnancy.…”

“…In contrast, Th-1 cytokines can induce trophoblast cell lysis and consequently fetal abortion. 3,[13][14][15]44 We found higher IL-4 and IL-10 levels in HIV-negative women compared with HIV-infected women throughout the study period. IFN-␥ levels did not differ between the 2 groups.…”

“…3 Thus, the thymus is reduced in size during pregnancy in various mammalian species, 4,5 and in mice this reduction is accompanied by a substantial loss of thymocyte proliferation and decreased thymic output. 6 In the present study, we did not expose the pregnant women to a computed tomography scan; therefore, thymic size was not evaluated.…”