Loss of Allospecific Activating Receptor Expressing NK Cells Results in Maternal Tolerance of the Aberrant Fetus

Background: Differences in maternal NK cell immunophenotypes predispose some mothers to neural tube defect (NTD) development in laboratory studies. Clinical studies have shown that mothers with high expression of NK cell allospecific activating receptors (NK-AAR’s) experience an unexplained high rate of first trimester spontaneous pregnancy loss. It remains unclear if these “spontaneous” losses result from direct interaction of maternal NK cells with an aberrant fetus leading to selective fetal absorption. In this report, we address the provocative hypothesis that loss of maternal NK-AAR’s will result in increased survival of fetuses with NTD’s.

Methods: We challenged this hypothesis in a B6 murine model of fetal neural tube teratogenesis via IP administration of valproic acid (VPA) to pregnant dams at E8. Maternal NK cells expressing the allospecific Ly49H activating receptor were knocked down by IP administration of Ly49H-specific mAb (3D10) on the prior day (E7). Control and L49H-depleted dams and fetuses were then evaluated for NTD prevalence at E14.

Results: Ly49H knockdown was highly effective in reducing the frequency of L49H+ NK cells to background levels throughout the study period. Accordingly, the prevalence of fetuses with NTD’s was twice as high in L49H-depleted dams when compared to controls given VPA alone (28.7% vs 14.5%, p<0.05). Overall litter sizes were unchanged between the groups.

Conclusion: These findings establish a functional link between expression of maternal AAR’s and maternal “tolerance” of the abnormal fetus. Further studies are needed to define mechanisms by which maternal NK cells recognize and prevent propagation of aberrant fetal development.

Presenting Author(s)

Katherine C. Ott, MD
Research Fellow
Center for Fetal Cellular and Molecular Therapy, Ann and Robert H. Lurie Children's Hospital
Ann and Robert H. Lurie Children's Hospital
Chicago, Illinois
Disclosure: No Financial Relationships Disclosed

Co-Author(s)

MO
Marc Oria, PhD
Postdoctoral Researcher
Center for Fetal and Placental Research, Division of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center
Cincinatti, Ohio
Disclosure: No Financial Relationships Disclosed
CR
Catherine Redden, MS
Research Associate
Center for Fetal Cellular and Molecular Therapy, Ann and Robert H. Lurie Children's Hospital
Chicago, Illinois
Disclosure: No Financial Relationships Disclosed
HK
Hee Kap Kang, PhD
Postdoctoral Researcher
Center for Fetal Cellular and Molecular Therapy, Ann and Robert H. Lurie Children's Hospital
Chicago, Illinois
Disclosure: No Financial Relationships Disclosed
ML
Morgan Langereis, MS
Research Associate
Center for Fetal Cellular and Molecular Therapy, Ann and Robert H. Lurie Children's Hospital
Chicago, Illinois
Disclosure: No Financial Relationships Disclosed
LT
Lucas Turner, BS
Research Associate
Center for Fetal Cellular and Molecular Therapy, Ann and Robert H. Lurie Children's Hospital
Chicago, Illinois
Disclosure: No Financial Relationships Disclosed
AA
Amir Alhajjat, MD
Attending Physician
Center for Fetal Cellular and Molecular Therapy, Ann and Robert H. Lurie Children's Hospital
Chicago, Illinois
Disclosure: No Financial Relationships Disclosed
Soner Duru, MD
Attending Physician
Center for Fetal and Placental Research, Division of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center
Cincinatti, Ohio
Disclosure: No Financial Relationships Disclosed
JP
Jose Peiro, MD
Attending Physician
Center for Fetal and Placental Research, Division of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center
Cincinatti, Ohio
Disclosure: No Financial Relationships Disclosed

Senior Author(s)

AS
Aimen Shaaban, MD, FAAP
Attending Physician
Center for Fetal Cellular and Molecular Therapy, Ann and Robert H. Lurie Children's Hospital
Chicago, Illinois
Disclosure: No Financial Relationships Disclosed