Tolerance to Noninherited Maternal MHC Antigens in Mice

Abstract

The phenomenon of tolerance to noninherited maternal Ags (NIMA) is poorly understood. To analyze the NIMA effect C57BL/6 (H-2b/b) males were mated with B6D2F1 (H-2b/d) females, whereby 50% of the offspring are H-2b/b mice that have been exposed to maternal H-2d alloantigens. Controls were H-2b/b offspring of C57BL/6 mothers, either inbred C57BL/6 mice or F1 backcross mice from breedings with H-2b/d fathers. We found that 57% of the H-2b/b offspring of semiallogeneic (H-2b/d) mothers accepted fully allogeneic DBA/2 (H-2d/d) heart grafts for >180 days, while similar transplants were all rejected by day 11 in controls (p < 0.0004). Foster nursing studies showed that both oral and in utero exposure to NIMA are required for this tolerogenic effect. An effect of NIMA was also found to extend the survival of skin grafts from a semiallogeneic donor (p < 0.02). Pretransplant analysis of splenocytes showed a 40–90% reduction of IL-2-, IL-5-, and IFN-γ-producing T cells responding to H-2d-expressing APC in NIMAd-exposed vs control mice. Injection of pregnant BALB/c-dm2 (H-2Ld-negative) female mice i.v. with H-2Ld61–80 peptide profoundly suppressed the offspring’s indirect pathway alloreactive CD4+ T cell response to H-2Ld. These results suggest that the natural exposure of the fetus and newborn to maternal cells and/or soluble MHC Ags suppresses NIMA-allospecific T cells of the offspring, predisposing to organ transplant tolerance in adult mice.

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

“…9 Likewise, hematopoietic 6,10 and nonhematopoietic 11 cells from maternal origin may persist into adulthood. The tolerogenic potential of chimerism, established either through bone marrow transplantation (macrochimerism) 12 or through pregnancy (microchimerism), 7 has been documented in both rodent 13,14 and in human transplantation settings. 15,16 We earlier described the presence of minor H antigen HA-1-specific T CTL , minor H antigen HA-1-specific T REG , and HA-1 ϩ circulating microchimeric cells in the setting of kidney transplantation.…”

Prediction of Reactivity to Noninherited Maternal Antigen in MHC-Mismatched, Minor Histocompatibility Antigen-Matched Stem Cell Transplantation in a Mouse Model

“…There have been several previously reported investigations of noninherited maternal Ags (NIMAs) (2,3). A reciprocal process, trafficking of maternal cells across the placenta, has also been documented (4,5) and can result in life-long microchimerism in the offspring (6).…”

Effects of Non-Inherited Parental Hla-Antigens Upon Immune Response in Progeny

“…Имеется предположение, что во время грудного вскармливания материнские клетки и HLA белки могут продолжать попадать к новорожденному и, возможно, таким образом, стимулировать толерант ность [20]. Как оказалось, существует положитель ный момент грудного вскармливания на приживле ние материнского почечного трансплантата у ребен ка [31].…”

“…Большой вклад в понимание этого феномена внесли работы W. J. Burlingham c коллегами (1998, 2003 гг. ) [20,28,29] и J.J. Van Rood с коллегами (1998 2005 гг.) [35,70,71,73,74,75].…”

“…Полностью аллогенные H2d/d васкулинизирован ные трансплантаты сердца были приняты только 50 % H2b/b мышами, а у другой половины мышей трансплантаты сердца были отторгнуты замедлен ным способом. Приживление пересадки кожи было только продлено, если донор был полуаллогенным (H2b/d), а отторжение наблюдалось при полной ал логенности трансплантата (H2d/d) [20]. Представ ленное экспериментальное исследование на мышах показало, что неунаследованные материнские MHC не создают на себя стойкой пренатальной толерант ности.…”