Adriana Déroche

Regulation of parental alloreactivity by reciprocal F1 hybrids. The role of lactation

Adult reciprocal F1 hybrids differ in their susceptibility to parental graft versus host (GvH) reactions. These reactions were lower when the donor strain was syngeneic with the maternal one. Splenocytes from the member of the reciprocal pair in which the GvH reactions were lower also induced a decreased response of parental cells in cytotoxicity assays and in mixed lymphocyte reactions (MLR). The treatment with anti-CD8 plus complement was able to abrogate the different stimulatory ability of the reciprocal F1 spleen populations. Foster-nursing of F1 hybrids on mothers from the paternal strain was able to induce permanent alterations in the ability of their splenocytes to induce both parental anti-F1 MLR and CTL. The stimulatory ability was indistinguishable from that observed in the reciprocal F1 combination nursed on its own mother. Moreover, lactation was able to alter the ability of CD8+ spleen cells to regulate CTL and parental anti-F1 MLR. The results reported herein show the existence of a maternal effect acting though milk capable of altering the regulation of parental alloreactive T reactions towards self histocompatibility antigens.

Early increase in graft-versus-host reactivity during pregnancy in the mouse

Alloreactive T levels of para-aortic lymph nodes (PALN) and spleen were determined on different days of pregnancy in BALB/c females by local and systemic graft-versus-host (GvH) assays. A significant increase in GvH reactivity was registered early in both allogeneic and syngeneic matings, operating not only towards paternal but also towards third party strains. Immunoregulatory mechanisms in PALN also involved the appearance of progressive suppression during the first days of pregnancy. The possible role of non-specific early increases in T alloreactivity in triggering suppressor mechanisms and the nature of the immunogens responsible for the alterations in GvH reactivity are discussed.

Maternal influence on the immune response: SMLC reactions between identical and reciprocal F1 hybrids and the role of lactation

Identical and reciprocal adult F1 mice from different strain combinations, either nursed on their own mothers or foster-nursed on mothers from the paternal strain, were used to carry out SMLC assays. The results obtained showed that: (1) in vitro proliferation of F1 T cells was significantly different when splenocytes from identical versus reciprocal hybrids were used as the stimulatory population, splenocytes from one of the members of the reciprocal pair being able to induce higher proliferative responses of T cells from both identical and reciprocal F1 hybrids; (2) foster-nursing of F1 hybrids on mothers from the paternal strain was able to induce permanent alterations in the ability of their splenocytes to stimulate the proliferation of responder F1 T cells. The stimulatory ability of splenocytes from foster-nursed hybrids was indistinguishable from that observed in the reciprocal F1 combination nursed by its own mother. The existence of a maternal effect acting through milk on the outcome of self recognition in the litter is discussed.

Neonatal cells in the immunoregulation of parental alloreactivity

The ability of neonatal murine F1 cells to regulate parental graft vs. host (GvH) reactions was investigated. Neonatal F1 splenocytes were able to decrease significantly the deleterious effects of systemic GvH reactions induced either with maternal or paternal splenocytes in a third party strain. Both neonatal F1 splenocytes or thymocytes were able to decrease local GvH reactions induced with maternal splenocytes towards paternal histocompatibility antigens. In the same experimental conditions, however, neonatal F1 cells were unable to decrease local GvH reactions induced with paternal splenocytes towards maternal histocompatibility antigens; using different numbers of neonatal F1 cells not only was no suppressive effect detected but even, a significant increase in GvH was registered. Similar results were obtained when mortality assays were carried out. It can be concluded that neonatal F1 mice differ in their capacity for regulating parental alloreactive T reactions against self histocompatibility antigens either of maternal or paternal origin.

Popliteal lymph node enlargement induced in syngeneic hosts by T cells from foster-nursed mice

Splenocytes from adult F1 mice were assayed for their capacity to induce popliteal lymph node enlargement (PLNE) when inoculated in the footpad of identical or reciprocal F1 hosts. The results obtained showed that: (i) T Lyt 1+ splenocytes from adult F1 hybrids were able to induce a significant PLNE when inoculated in reciprocal but not in identical F1 hosts. (ii) Foster-nursing of F1 hybrids on mothers from the paternal strain was able to induce permanent alterations in the ability of their T splenocytes to induce PLNE: Lyt 1+ splenocytes were able to induce significant PLNE in identical but not in reciprocal F1 hosts. Thus, the ability of T splenocytes from foster-nursed F1 hybrids to induce PLNE resembled that observed in reciprocal F1 hybrids nursed by their own mothers. (iii) PLNE was accompanied by cell proliferation involving host B and T lymphocytes. (iv) This PLNE could be detected using F1 hybrids from parental strains differing or not at H-2 antigens but involving a parental strain expressing the stimulatory Mlsa allele and a parental strain bearing the nonstimulatory Mlsb allele while it was not observed in F1 hybrids from parental strains sharing Mlsa antigens.

Maternal immunoregulation: interrelationship between alloreactive and anti-self plus conventional antigen T sets of cells

In a previous paper we reported early immunoregulatory mechanisms involving not only the appearance of progressive suppression but also significant increases in alloreactive T levels in paraaortic lymph nodes (PALN) and spleen, not only in allogeneic but also in syngeneic pregnancies. Taking into account the hypothesis of the superposition of the alloreactive and the anti-self plus conventional antigens T sets of cells, we investigated whether immunization with conventional antigens was able to alter alloreactive T levels. Weekly i.p. doses of rabbit red bloods cells (RRBC) in BALB/c mice resulted in a dose-dependent increase in spleen alloreactivity as determined by graft-versus-host (GvH) assays in strain combinations differing at H-2 level but not in those sharing the same H-2 with BALB/c. The increases could be significantly decreased by an anti-idiotype anti-RRBC serum. Pretreatment with i.p. weekly doses of sheep red blood cells (SRBC) before mating was able to induce dose-dependent fetal damage when the parents differed at the H-2 level. SRBC immunization in one of the uterine horns induced increases in PALN weight which were much higher in progesterone-pseudopregnant than in virgin mice; T alloreactivity was significantly increased in the draining PALN only in pseudopregnant females. These results favour the postulation of the superposition between the alloreactive and the anti-self plus conventional antigens T sets of cells and suggest a possible role for conventional fetal antigens (non H-2) in triggering immunoregulatory mechanisms operating in pregnancy.

Long-lasting functional unresponsiveness induced by a milk-transmitted Mls-1a-like superantigen.

We have recently shown (Piazzon et al. (1994) J. Immunol. 153, 1553) that foster-nursing of BALB/c mice on F1 Mls-1bxa mothers induce the progressive deletion of V beta 6+ and 8.1+ T cells in 50% of the mice. Preceding clonal deletion, a state of functional inactivation of CD4+ T cells to Mls-1a and anti-V beta 6 antibodies was detected in young mice. In the present paper we show that foster-nursing of BALB/c mice on (BALB/cxAKR)FI mothers is able to induce alterations in T cell reactivity in the non-deletor mice. Lymph node cells from foster-nursed mice show a decreased proliferative level against anti-V beta 6 antibodies and a diminished response in MLR and in CTL assays. The proliferative responses to either OVA or Con-A are also reduced. This state of functional inactivation is detected even in 6-month-old foster-nursed mice. Thus, the transmission through milk of the Mls-1a-like superantigen correlates in the non-deletor mice with a long-lasting state of functional inactivation and a decreased immune reactivity.

Neonatal thymic contrasuppressor activity on graft versus host reactions towards self histocompatibility antigens. Parental effects

The ability of fetal and neonatal F1 thymocytes to regulate parental graft versus host (GvH) reactions against self histocompatibility antigens was investigated. The results obtained showed that: (1) fetal F1 thymocytes were able to suppress both maternal and paternal GvH reactivity; (2) at birth, thymocytes were still able to suppress maternal GvH reactivity while no suppression of paternal reactions was detected; the ability to suppress maternal GvH reactions could be detected until day 3; (3) the loss of suppressor activity correlated with the ability of thymocytes to contrasuppress parental GvH reactions. Thus, 24-h F1 thymocytes showed contrasuppressor activity on paternal GvH reactivity and 4-day thymocytes on maternal reactivity. Thymic cells with contrasuppressor activity were shown to be Lyt-1+, CD4+, CD8- and adherent to Vicia villosa. These results suggest the existence of parental effects influencing the duration of thymic suppression and the subsequent appearance of contrasuppressor activity on GvH reactions against self histocompatibility antigens, according to the maternal or paternal origin of self antigens towards which the reaction is directed.