TY - JOUR
T1 - Maternal microchimerism and cell-mediated immune-modulation enhance engraftment following semi-allogenic intrauterine transplantation
AU - Kandasamy, Karthikeyan
AU - Tan, Lay Geok
AU - B. Johana, Nuryanti
AU - Tan, Yi Wan
AU - Foo, Wanling
AU - Yeo, Julie S.L.
AU - Ravikumar, Vikashini
AU - Ginhoux, Florent
AU - Choolani, Mahesh
AU - Chan, Jerry K.Y.
AU - Mattar, Citra N.Z.
N1 - Publisher Copyright:
© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Successful intrauterine hematopoietic cell transplantation (IUT) for congenital hemoglobinopathies is hampered by maternal alloresponsiveness. We investigate these interactions in semi-allogenic murine IUT. E14 fetuses (B6 females × BALB/c males) were each treated with 5E+6 maternal (B6) or paternal (BALB/c) bone marrow cells and serially monitored for chimerism (>1% engraftment), trafficked maternal immune cells, and immune responsiveness to donor cells. A total of 41.0% of maternal IUT recipients (mIUT) were chimeras (mean donor chimerism 3.0 ± 1.3%) versus 75.0% of paternal IUT recipients (pIUT, 3.6 ± 1.1%). Chimeras showed higher maternal microchimerism of CD4, CD8, and CD19 than non-chimeras. These maternal cells showed minimal responsiveness to B6 or BALB/c stimulation. To interrogate tolerance, mIUT were injected postnatally with 5E+6 B6 cells/pup; pIUT received BALB/c cells. IUT-treated pups showed no changes in trafficked maternal or fetal immune cell levels compared to controls. Donor-specific IgM and IgG were expressed by 1%-3% of recipients. mIUT splenocytes showed greater proliferation of regulatory T cells (Treg) upon BALB/c stimulation, while B6 stimulation upregulated the pro-inflammatory cytokines more than BALB/c. pIUT splenocytes produced identical Treg and cytokine responses to BALB/c and B6 cells, with higher Treg activity and lower pro-inflammatory cytokine expression upon exposure to BALB/c. In contrast, naïve fetal splenocytes demonstrated greater alloresponsiveness to BALB/c compared to B6 cells. Thus pIUT, associated with increased maternal cell trafficking, modulates fetal Treg, and cytokine responsiveness to donor cells more efficiently than mIUT, resulting in improved engraftment. Paternal donor cells may be considered alternatively to maternal donor cells for intrauterine and postnatal transplantation to induce tolerance and maintain engraftment.
AB - Successful intrauterine hematopoietic cell transplantation (IUT) for congenital hemoglobinopathies is hampered by maternal alloresponsiveness. We investigate these interactions in semi-allogenic murine IUT. E14 fetuses (B6 females × BALB/c males) were each treated with 5E+6 maternal (B6) or paternal (BALB/c) bone marrow cells and serially monitored for chimerism (>1% engraftment), trafficked maternal immune cells, and immune responsiveness to donor cells. A total of 41.0% of maternal IUT recipients (mIUT) were chimeras (mean donor chimerism 3.0 ± 1.3%) versus 75.0% of paternal IUT recipients (pIUT, 3.6 ± 1.1%). Chimeras showed higher maternal microchimerism of CD4, CD8, and CD19 than non-chimeras. These maternal cells showed minimal responsiveness to B6 or BALB/c stimulation. To interrogate tolerance, mIUT were injected postnatally with 5E+6 B6 cells/pup; pIUT received BALB/c cells. IUT-treated pups showed no changes in trafficked maternal or fetal immune cell levels compared to controls. Donor-specific IgM and IgG were expressed by 1%-3% of recipients. mIUT splenocytes showed greater proliferation of regulatory T cells (Treg) upon BALB/c stimulation, while B6 stimulation upregulated the pro-inflammatory cytokines more than BALB/c. pIUT splenocytes produced identical Treg and cytokine responses to BALB/c and B6 cells, with higher Treg activity and lower pro-inflammatory cytokine expression upon exposure to BALB/c. In contrast, naïve fetal splenocytes demonstrated greater alloresponsiveness to BALB/c compared to B6 cells. Thus pIUT, associated with increased maternal cell trafficking, modulates fetal Treg, and cytokine responsiveness to donor cells more efficiently than mIUT, resulting in improved engraftment. Paternal donor cells may be considered alternatively to maternal donor cells for intrauterine and postnatal transplantation to induce tolerance and maintain engraftment.
KW - bone marrow cells
KW - fetal therapy
KW - hematopoietic stem and progenitor cells
KW - intrauterine transplantation
KW - maternal donor cells
KW - paternal donor cells
KW - semi-allogenic donor cells
UR - http://www.scopus.com/inward/record.url?scp=85101467218&partnerID=8YFLogxK
U2 - 10.1096/fj.202002185RR
DO - 10.1096/fj.202002185RR
M3 - Article
C2 - 33570785
AN - SCOPUS:85101467218
SN - 0892-6638
VL - 35
JO - FASEB Journal
JF - FASEB Journal
IS - 3
M1 - e21413
ER -