Abstract: Intrauterine hematopoietic cell transplantation (IUT), potentially curative in congenital haematological disease, is limited by subtherapeutic donor cell chimerism. Microchimerism of maternal immune cells trafficked into IUT recipients may directly influence donor-specific alloresponsiveness. We investigated if maternal dendritic cell (DC) depletion affected recipient alloresponsiveness and donor cell chimerism. IUT was performed on fetuses at embryonic day 14 (E-14), after crossing transgenic CD11c.DTR (C57BL/6) female mice and BALB/c male mice, with semi-allogenic BALB/c or C57BL/6, or fully allogenic C3H bone marrow donor cells, following transient maternal DC depletion with diphtheria toxin administered to the dam. We observed reduced maternally trafficked cells in the recipient fetuses particularly following BALB/c donor cell transplantation. IUT enriched trafficked maternal-derived clonotypes which displayed substantially reduced diversity. DC depletion restored maternal clonotype diversity and enhanced donor-specific immunomodulatory changes in the recipient pups, increasing regulatory T-cell subtype and immune-inhibitory protein expression, and inhibiting proinflammatory cytokine and donor-specific antibody production, though it did not affect donor cell chimerism. Functional tolerance acquired after BALB/c donor cell IUT with DC depletion was maintained following postnatal transplantation without immunosuppression, despite diminishing peripheral blood donor chimerism. We show for the first time that trafficked maternal cells influences donor-specific alloresponsiveness to IUT, possibly by expanding alloreactive clonotypes in the recipients, and depleting maternal DC promotes and maintains acquired tolerance independent of donor cell chimerism, presenting a novel approach to improve IUT efficacy.

Journal Link: 10.21203/rs.3.rs-1675044/v1 Journal Link: Publisher Website Journal Link: Download PDF Journal Link: Google Scholar