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Title: The in vitro interrogation of the immune system in pregnancy
Author: Shah, Nishel
ISNI:       0000 0004 6421 0955
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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The maternal immune system is unique and complex due to the influence of maternal and fetal compartments on each other. Researchers have postulated mechanisms that enable the feto-placental unit to escape maternal immune recognition and maternal adaptations to protect the fetus. Despite these, pregnant women can mount strong immune responses to infecting organisms. In order to profile the changes observed in uncomplicated pregnancies, longitudinal peripheral blood including delivery and postnatal samples were obtained. In a separate cohort, labour peripheral blood, cord blood and myometrial samples were obtained. Combination of IFN-γ, IL-10, IL-4 and granzyme B ELISpot data, flow cytometry, and lymphoproliferative and multiplex assays were analysed. Collectively the data indicates an activated immune system (CD38, IFN-γ) during pregnancy, with simultaneous negative regulation of responder T cells (IL-10) that reverses in late pregnancy. Parturition is accompanied by a loss of Treg mediated tolerance with suppression of immune activation. In a further study patients receiving progesterone or RU486 treatment in pregnancy were recruited to study the immunological effects of progesterone. Data revealed progesterone reduces IFN-γ and granzyme B T cell responses in vitro. Achieving this by a combination of altered memory T cell antigen sensitivity (effector memory/EM, and terminally differentiated effector memory/TEMRA subsets), leukocyte migration (CCR3, CCR6), and negative regulation of apoptosis and exhaustion (CD95, PD-1, CD57). Advancing pregnancy may be associated with an inherent loss of sensitivity to progesterone. Finally, to understand the effects of immunisation, pregnant and control subjects immunised against influenza were recruited. Ex vivo antibody and in vitro antigen specific pregnancy response to immunisation are comparably potent in both. However, this is achieved through different mechanisms of T cell, CTL and APC regulation. Thus, the maternal immune system is partly regulated by progesterone, which has suppressive quality. However, immuno-modulation in pregnancy is complex and antigen responses vary when compared to non-pregnant individuals.
Supervisor: Johnson, Mark ; Imami, Nesrina Sponsor: Borne
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral