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Conference paperMacharia G, Staller E, Yue L, et al., 2018,
Infection With Multiple Transmitted/Founder (TF) HIV-1 Viruses Impacts Peak VL and HIV-1 Pathogenesis
, HIV Research for Prevention 2018: AIDS Vaccine, Microbicide and ARV-based Prevention Science (HIVR4P) -
Journal articleShah NM, Imami N, Johnson MR, 2018,
Progesterone Modulation of Pregnancy-Related Immune Responses
, FRONTIERS IN IMMUNOLOGY, Vol: 9, ISSN: 1664-3224Progesterone (P4) is an important steroid hormone for the establishment and maintenance of pregnancy and its functional withdrawal in reproductive tissue is linked with the onset of parturition. However, the effects of P4 on adaptive immune responses are poorly understood. In this study, we took a novel approach by comparing the effects of P4 supplementation longitudinally, with treatment using a P4 antagonist mifepristone (RU486) in mid-trimester pregnancies. Thus, we were able to demonstrate the immune-modulatory functions of P4. We show that, in pregnancy, the immune system is increasingly activated (CD38, CCR6) with greater antigen-specific cytotoxic T cell responses (granzyme B). Simultaneously, pregnancy promotes a tolerant immune environment (IL-10 and regulatory-T cells) that gradually reverses prior to the onset of labor. P4 suppresses and RU486 enhances antigen-specific CD4 and CD8 T cell inflammatory cytokine (IFN-γ) and cytotoxic molecule release (granzyme B). P4 and RU486 effectively modulate immune cell-mediated interactions, by regulating differentiated memory T cell subset sensitivity to antigen stimulation. Our results indicate that P4 and RU486, as immune modulators, share a reciprocal relationship. These data unveil key contributions of P4 to the modulation of the maternal immune system and suggests targets for future modulation of maternal immune function during pregnancy.
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Journal articleKelleher P, Xu X-N, 2018,
Hard-to-kill macrophages lead to chronic inflammation in HIV.
, Nat Immunol, Vol: 19, Pages: 433-434 -
Journal articleCowman SA, Jacob J, Hansell DM, et al., 2018,
Whole blood gene expression in pulmonary non-tuberculous mycobacterial infection
, American Journal of Respiratory Cell and Molecular Biology, Vol: 58, Pages: 510-518, ISSN: 1044-1549RATIONALE: The factors predisposing towards the development of pulmonary non-tuberculous mycobacterial disease (pNTM) and influencing disease progression remain unclear. Impaired immune responses have been reported in individuals with pNTM but data are limited and inconsistent. OBJECTIVES: To use gene expression profiling to examine the host response to pNTM. METHODS: Microarray analysis of whole blood gene expression was performed on 25 subjects with pNTM and 27 uninfected controls with respiratory disease. Gene expression results were compared to phenotypic variables and survival data. MEASUREMENTS AND MAIN RESULTS: Compared with uninfected controls, pNTM was associated with down-regulation of 213 transcripts enriched for terms related to T cell signalling including IFNG. Reduced IFNG expression was associated with more severe CT changes and impaired lung function. Mortality was associated with the expression of transcripts related to the innate immune response and inflammation, whereas transcripts related to T and B cell function were associated with improved survival. CONCLUSIONS: These findings suggest that pNTM is associated with an aberrant immune response which may reflect an underlying propensity to infection, or result from NTM infection itself. There were important differences in the immune response associated with survival and mortality in pNTM.
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Conference paperShah NM, Edey L, Sooranna G, et al., 2018,
Labour is associated with a decline in Treg function and their modulation of TLR-Ligand induced immune responses
, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Sage Publications Inc., Pages: 314A-314A, ISSN: 1071-5576 -
Conference paperSassine AJ, Sivarajasingam SP, Cocker ATH, et al., 2018,
Erythrocyte oleic acid is correlated with increasing natural killer cells in maternal blood
, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Elsevier, Pages: 319A-319A, ISSN: 1933-7191 -
Conference paperSivarajasingam SP, Cocker ATH, Sassine AJ, et al., 2018,
Disrupted immunological equilibrium of decidual natural killer cells and regulatory T cells with onset of labour
, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Elsevier, Pages: 177A-177A, ISSN: 1071-5576 -
Conference paperCocker A, Sivarajasingam S, Dermont S, et al., 2018,
Gestational immunological adaptations and anti-viral responses are disrupted in HIV-1+pregnancies
, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Elsevier, Pages: 318A-319A, ISSN: 1933-7191 -
Conference paperShah NM, Sooranna G, Imami N, et al., 2018,
Progesterone suppressed ex vivo pregnancy immune responses are reversed with the progesterone antagonist RU486
, 65th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: Sage, Pages: 314A-314A, ISSN: 1933-7191 -
Journal articleShah NM, Herasimtschuk AA, Boasso A, et al., 2017,
Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation.
, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner. We analyzed changes in surface markers of peripheral blood T cells, ex vivo antigen-specific T cell responses, indoleamine 2,3-dioxygenase (IDO) activity (kynurenine/tryptophan ratio, KTR), plasma neopterin concentration, and the in vitro expression of progesterone-induced blocking factor (PIBF) in response to peripheral blood mononuclear cell culture with progesterone. We found that mid gestation is characterized by reduced antigen-specific T cell responses associated with (1) predominance of effector memory over other T cell subsets; (2) upregulation of inhibitory markers (programmed death ligand 1); (3) heightened response to progesterone (PIBF); and (4) reduced proportions of myeloid DC and concurrent IDO activity (KTR). Conversely, antigen-specific T cell responses normalized in late pregnancy and were associated with increased markers of T cell activation (CD38, neopterin). However, these changes occur with a simultaneous upregulation of immune suppressive mechanisms including apoptosis (CD95), coinhibition (TIM-3), and immune regulation (IL-10) through the course of pregnancy. Together, our data suggest that immune tolerance dominates in the second trimester and that it is gradually reversed in the third trimester in association with immune activation as the end of pregnancy approaches.
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