The survival of the fetal allograft is a remarkable phenomenon. The fetus contains a complement of paternal antigens, up to half of which are likely to be “foreign” to the mother. Mothers will reject grafts from their children. Yet, these same children were carried for nine months as “fetal allografts” and managed to escape rejection. Understanding of this phenomenon is incomplete but may be approached through brief analysis of the immunologic mechanisms of graft rejection and regulation of these immune mechanisms.
Mechanisms of Graft Rejection
Rejection of grafts identified as allogeneic (meaning from the same species but from a different donor not an identical twin to the recipient) is effected by recognition that the donor contains certain cell surface antigens, called major histocompatibility complex (MHC) antigens, which differ from the hosts. Recognition of these antigens is mediated by lymphocytes, probably with macrophage cooperation. These “afferent limb” lymphocytes then find their way to draining lymph nodes, where they probably divide and give rise to clones of lymphocytes or recruit lymphocytes capable of recognizing these MHC antigens on the surface of the grafted cells. In the “efferent (or effector) limb” of graft rejection, these activated lymphocytes accumulate in the graft tissues, where it appears that they recognize cells bearing the MHC antigens to which they had been sensitized. Some of these effector lymphocytes are able to lyse cells displaying these target antigens. Other lymphocytes may be stimulated to release soluble factors, lympho-Idnes, which attract other cells, including phagocytic cells, into these tissues. Certain MHC antigens, class 1 antigens (HLA-A,B,C), seem to be the targets for lysis; other antigens, class 2 antigens (HLA-D/DR), seem to be able to stimulate allogeneic lymphocytes to divide.
Although antibody to allogeneic antigens is produced during engraftment, the role of these antibodies in facilitating most instances of graft rejection is uncertain. Thus, graft rejection is mediated primarily by cells. Why is the fetus containing numerous “foreign” MHC and other antigens not rejected during pregnancy?
Failure of Graft Rejection during Pregnancy
One possibility is that the fetus and its placental tissues are within an immunologically protected environment. This could be accomplished by barriers to the transplacental passage of cells, antigens (and antibody). Another possibility is that cells of fetal origin are somehow resistant to immunologic effector mechanisms. Conceivably, this resistance could be mediated by local humoral mechanisms or by the absence or masking of target antigens for graft rejection on the fetal cells. A third possible mechanism for graft tolerance is that there is suppression of the maternal immune response, which results in a failure of graft rejection. This suppression could be mediated by maternal mechanisms or by factors produced by the fetus or placenta.
Attempts to demonstrate a functional placental barrier to maternal host defense mechanisms have been largely unsuccessful. Fetal blood cells gain access to maternal circulation. Maternal serums contain antibody to fetal MHC antigens, suggesting that sensitization to fetal antigens occurs during pregnancy. Thus, the placenta is not an immunologically privileged site. Fetal resistance to immune mechanisms is another potential mechanism for tolerance of the fetus. In a preliminary report, a protein fraction isolated from trophoblast cell membranes has been shown to specifically inhibit lymphocyte proliferative responses to allogeneic cells but not to mitogens. Conceivably, this substance might block local recognition of fetal MHC antigens. The presence of MHC antigens on fetal and trophoblast cells has been demonstrated, but the density of these antigens on trophoblast cell surfaces is low. Masking of these antigens has been suggested by some studies but not by others.
Immune Responses during Pregnancy
There is evidence that maternal immune responses are diminished during pregnancy. The ability of lymphocytes to divide in response to certain stimuli has been measured during pregnancy, and although studies of lymphocyte proliferative responses to mitogens during pregnancy have shown conflicting results, maternal lymphocytes obtained during the second and third trimester show diminished proliferative responses to soluble antigens and diminished proliferation in response to allogeneic lymphocytes. Cell-mediated cytotoxicity, the ability of lymphocytes to kill allogeneic or viral infected cells, is also diminished during pregnancy. T-lymphocytes can be separated according to the presence of specific antigenic determinants on their cell surface into helper and suppressor lymphocytes. Helper lymphocytes, as their name suggests, can aid or augment certain immune responses (including the cytotoxic response important for graft rejection); in contrast, suppressor lymphocytes can regulate or diminish certain immune responses. When lymphocytes of pregnant women were analyzed for the distribution of helper and suppressor phenotypes, decreased numbers of T-helper lymphocytes were found.
There is also evidence that soluble factors present in maternal serum can mediate immunosuppression. The maternal lymphocyte proliferative response to alloan-tigens can be blocked by maternal serum. Maternal serum can also block the secretion of the lymphokine macrophage inhibitory factor in response to allogeneic cells. It appears that some of this serum effect is mediated by IgG antibody possibly directed against HLA-D/DR antigens.
Other factors in serum are also potentially immunosuppressive. Progesterone can limit lymphocyte proliferative responses to mitogens and alloantigens in concentrations readily achieved in pregnancy serum. Less pronounced effects can be produced by achievable concentrations of estradiol and cortisol. Corticosteroids also inhibit macrophage functions such as lymphokine responsiveness and phagocytosis. Other components of pregnancy serum, including human chorionic gonadotropin and a-fetoprotein, also may be immunosuppressive. Other serum factors of pregnancy, pregnancy-associated glycoproteins, have been shown to inhibit lymphocyte proliferation and cytotoxicity. Last, fetal lymphocytes (obtained from human cord blood) can suppress adult T-lymphocyte proliferation and thus may inhibit the maternal immune response.
These studies suggest that tolerance of the fetal allograft may be mediated in part by suppression of the maternal immune response. Whereas this is obviously beneficial to the fetus, suppression of cell-mediated immunity might also result in susceptibility to a variety of pathogens. The occurrence of certain infections among persons with well-defined impairments of cell-mediated immunity and the results of studies with experimental animals have demonstrated that the cell-mediated immune system is of critical importance in the defense against certain organisms. Certain fungi, notably Cryptococcus neoformans andCandida albicans, are more common pathogens in the setting of impaired cell-mediated immunity. Certain protozoa, notably Pneumocystis carinii and Toxoplasma gondii, are opportunistic pathogens among patients with diminished cell-mediated immunity. Bacteria which are predominantly intracellular pathogens, such as Listeria monocytogenes, and mycobacteria such as Mycobacterium tuberculosis, often produce disease, and viral infections, notably cytomegalovirus and herpes simplex virus, often complicate the course of patients with impaired cell-mediated immunity. The question today is whether pregnancy is associated with either a greater risk of or increased morbidity due to infection with any of these agents. This presentation will address the issue of viral infection in pregnancy.