Implantation involves an initial pro-inflammatory response
2020; Elsevier BV; Volume: 114; Issue: 2 Linguagem: Inglês
10.1016/j.fertnstert.2020.05.039
ISSN1556-5653
Autores Tópico(s)Ectopic Pregnancy Diagnosis and Management
ResumoImmunological causes and treatment for reproductive failure are the subject of considerable debate (1Odendaal J. Quenby S. Sammaritano L. Macklon N. Branch D.W. Rosenwaks Z. Immunologic and rheumatologic causes and treatment of recurrent pregnancy loss: what is the evidence?.Fertil Steril. 2019; 112: 1002-1012Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). The majority of studies investigating the reproductive immunology of early human pregnancy find changes in immune biomarkers in early pregnancy (1Odendaal J. Quenby S. Sammaritano L. Macklon N. Branch D.W. Rosenwaks Z. Immunologic and rheumatologic causes and treatment of recurrent pregnancy loss: what is the evidence?.Fertil Steril. 2019; 112: 1002-1012Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). Most studies also find differences in immune biomarkers in successful pregnancy that are not present in reproductive failure or control patients (1Odendaal J. Quenby S. Sammaritano L. Macklon N. Branch D.W. Rosenwaks Z. Immunologic and rheumatologic causes and treatment of recurrent pregnancy loss: what is the evidence?.Fertil Steril. 2019; 112: 1002-1012Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). The consistent finding of immune biomarker differences means that the need for a precision medicine approach for improving reproductive outcomes is widely recognized (1Odendaal J. Quenby S. Sammaritano L. Macklon N. Branch D.W. Rosenwaks Z. Immunologic and rheumatologic causes and treatment of recurrent pregnancy loss: what is the evidence?.Fertil Steril. 2019; 112: 1002-1012Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). A precision medicine approach would involve a screening test that determines which women could benefit from immunomodulation. Then a randomized controlled trial including screen-positive women that demonstrates that the immune intervention improved reproductive outcomes would be needed. Unfortunately, this stratified approach has not yet succeeded in terms of large-scale, multicenter trials that demonstrate clinical efficacy (1Odendaal J. Quenby S. Sammaritano L. Macklon N. Branch D.W. Rosenwaks Z. Immunologic and rheumatologic causes and treatment of recurrent pregnancy loss: what is the evidence?.Fertil Steril. 2019; 112: 1002-1012Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). A reason for this lack of clinical progress is the difficulty in translating laboratory science into clinical tests that allow effective precision medicine. The paper by Zhang et al. (2Zhang T. Zhu W. Zhao Y. Cheung W.C. Liu Y. Chen X. et al.Early transient suppression of immune 1 checkpoint proteins Tim-3 and PD-1 in peripheral blood lymphocytes after blastocyst transfer is associated with successful implantation.Fertil Steril. 2020; 114: 426-435Scopus (2) Google Scholar) is an example of high-quality translational medicine that will facilitate a precision medicine approach. Zhang et al. found a reduction in T-cell immunoglobulin mucin-3 (Tim-3) and programmed death 1 (PD-1) expression in peripheral lymphocytes on days 3 and 6 after successful blastocyst implantation. As Tim-3 and PD-1 are important in anti-inflammatory pathways, this early maternal immune response to successful implantation is pro-inflammatory. The Zhang et al. (2Zhang T. Zhu W. Zhao Y. Cheung W.C. Liu Y. Chen X. et al.Early transient suppression of immune 1 checkpoint proteins Tim-3 and PD-1 in peripheral blood lymphocytes after blastocyst transfer is associated with successful implantation.Fertil Steril. 2020; 114: 426-435Scopus (2) Google Scholar) finding is counter to the concept that as there is a need for a maternal anti-inflammatory response to allow the semi-allogeneic embryo to evade the maternal immune response (1Odendaal J. Quenby S. Sammaritano L. Macklon N. Branch D.W. Rosenwaks Z. Immunologic and rheumatologic causes and treatment of recurrent pregnancy loss: what is the evidence?.Fertil Steril. 2019; 112: 1002-1012Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). The pro-inflammatory response to successful implantation was then followed by an anti-inflammatory response (2Zhang T. Zhu W. Zhao Y. Cheung W.C. Liu Y. Chen X. et al.Early transient suppression of immune 1 checkpoint proteins Tim-3 and PD-1 in peripheral blood lymphocytes after blastocyst transfer is associated with successful implantation.Fertil Steril. 2020; 114: 426-435Scopus (2) Google Scholar). The study of the endometrial preparation for pregnancy, decidualization, has also shown that pro-inflammatory followed by anti-inflammatory pathways are needed for successful implantation. Decidualization of endometrial stromal cells starts with recruitment and differentiation of circulating bone marrow−derived mesenchymal stem cells (3Tewary S. Lucas E.S. Fujihara R. Kimani P.K. Polanco A. Brighton P.J. et al.Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells: a randomised, double-blind placebo-controlled feasibility trial.EBioMedicine. 2020; 51: 102597Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). At the start of decidualization, there is an acute release of pro-inflammatory mediators (4Salker M.S. Nautiyal J. Steel J.H. Webster Z. Šućurović S. Nicou M. et al.Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss.PLoS One. 2012; 7e52252Crossref PubMed Scopus (131) Google Scholar) coinciding with the implantation window (4Salker M.S. Nautiyal J. Steel J.H. Webster Z. Šućurović S. Nicou M. et al.Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss.PLoS One. 2012; 7e52252Crossref PubMed Scopus (131) Google Scholar, 5Lucas E.S. Vrljicak P. Muter J. Diniz-da-Costa M.M. Brighton P.J. Kong C.-S. et al.Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window.Commun Biol. 2020; 3: 37Crossref PubMed Scopus (40) Google Scholar). After approximately 4 days of this inflammatory environment, anti-inflammatory decidual cells emerge. These anti-inflammatory cells are responsive to embryonic signals (5Lucas E.S. Vrljicak P. Muter J. Diniz-da-Costa M.M. Brighton P.J. Kong C.-S. et al.Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window.Commun Biol. 2020; 3: 37Crossref PubMed Scopus (40) Google Scholar). Other stromal cells fail to differentiate and emerge as senescent decidual cells (5Lucas E.S. Vrljicak P. Muter J. Diniz-da-Costa M.M. Brighton P.J. Kong C.-S. et al.Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window.Commun Biol. 2020; 3: 37Crossref PubMed Scopus (40) Google Scholar). Senescent decidual cells are progesterone resistant and secrete a complex mixture of extracellular matrix proteins and proteinases, pro-inflammatory cytokines, and chemokines, which induce secondary senescence in neighboring decidual cells (5Lucas E.S. Vrljicak P. Muter J. Diniz-da-Costa M.M. Brighton P.J. Kong C.-S. et al.Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window.Commun Biol. 2020; 3: 37Crossref PubMed Scopus (40) Google Scholar). Progesterone-dependent decidual cells can escape the fate of senescence by co-opting uNK cells to eliminate their senescent counterparts (5Lucas E.S. Vrljicak P. Muter J. Diniz-da-Costa M.M. Brighton P.J. Kong C.-S. et al.Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window.Commun Biol. 2020; 3: 37Crossref PubMed Scopus (40) Google Scholar). Successful implantation is a result of an initial dominance of pro-inflammatory senescent stromal cells followed by anti-inflammatory progesterone-dependent decidual cell survival. Lack of progesterone from the corpus luteum leads to excessive senescent cells, decidual breakdown, and menstruation. Progesterone secretion in response to HCG from the early embryo supports anti-inflammatory cells to maintain the decidua so that it can support pregnancy (5Lucas E.S. Vrljicak P. Muter J. Diniz-da-Costa M.M. Brighton P.J. Kong C.-S. et al.Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window.Commun Biol. 2020; 3: 37Crossref PubMed Scopus (40) Google Scholar). The finding of an initial short (3−6 days) pro-inflammatory followed up an anti-inflammatory immune response to implantation in both the endometrial stromal cells and the peripheral blood Tim-3 and PD-1 leucocyte expression is important clinically. First, timing of any immune therapies is critical. This is especially important in the field of reproduction, where millions of dollars are spent on indiscriminate immunosuppression (1Odendaal J. Quenby S. Sammaritano L. Macklon N. Branch D.W. Rosenwaks Z. Immunologic and rheumatologic causes and treatment of recurrent pregnancy loss: what is the evidence?.Fertil Steril. 2019; 112: 1002-1012Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). Second, the inflammatory changes in peripheral blood and decidua that lead to pregnancy support or failure are subtle and require targeted interventions. Third, the similarities in the timing of the pro- then anti-inflammatory response to implantation in the peripheral lymphocytes and decidual stromal cells raise the possibility of a blood test that gives clinical insight into endometrial function. A blood test is very desirable for patients, as it avoids endometrial biopsies and allows serial testing and monitoring in early pregnancy. The paper by Zhang et al. (2Zhang T. Zhu W. Zhao Y. Cheung W.C. Liu Y. Chen X. et al.Early transient suppression of immune 1 checkpoint proteins Tim-3 and PD-1 in peripheral blood lymphocytes after blastocyst transfer is associated with successful implantation.Fertil Steril. 2020; 114: 426-435Scopus (2) Google Scholar) adds to the growing body of work that is a prelude for a precision medicine future for reproduction. Small feasibility studies for such an approach (3Tewary S. Lucas E.S. Fujihara R. Kimani P.K. Polanco A. Brighton P.J. et al.Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells: a randomised, double-blind placebo-controlled feasibility trial.EBioMedicine. 2020; 51: 102597Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar) need to be confirmed in larger clinical trials. Early transient suppression of immune checkpoint proteins T-cell immunoglobulin mucin-3 and programmed cell death-1 in peripheral blood lymphocytes after blastocyst transfer is associated with successful implantationFertility and SterilityVol. 114Issue 2PreviewTo compare the changing peripheral levels of immune checkpoint proteins T-cell immunoglobulin mucin-3 (Tim-3)/galectin-9 (Gal-9), and programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) over a 9-day period after blastocyst transfer between women who did and did not conceive. Full-Text PDF
Referência(s)