The Role of Extracellular Vesicles and PIBF in Embryo-Maternal Immune-Interactions

Pregnancy represents a unique immunological situation. Though paternal antigens expressed by the conceptus are recognized by the immune system of the mother, the immune response does not harm the fetus. Progesterone and a progesterone induced protein; PIBF are important players in re-adjusting the functioning of the maternal immune system during pregnancy. PIBF expressed by peripheral pregnancy lymphocytes, and other cell types, participates in the feto-maternal communication, partly, by mediating the immunological actions of progesterone. Several splice variants of PIBF were identified with different physiological activity. The full length 90 kD PIBF protein plays a role in cell cycle regulation, while shorter splice variants are secreted and act as cytokines. Aberrant production of PIBF isoforms lead to the loss of immune-regulatory functions, resulting in and pregnancy failure. By up regulating Th2 type cytokine production and by down-regulating NK activity, PIBF contributes to the altered attitude of the maternal immune system. Normal pregnancy is characterized by a Th2-dominant cytokine balance, which is partly due to the action of the smaller PIBF isoforms. These bind to a novel form of the IL-4 receptor, and induce increased production of IL-3, IL-4, and IL-10. The communication between the conceptus and the mother is established via extracellular vesicles (EVs). Pre-implantation embryos produce EVs both in vitro, and in vivo. PIBF transported by the EVs from the embryo to maternal lymphocytes induces increased IL-10 production by the latter, this way contributing to the Th2 dominant immune responses described during pregnancy

The Role of Extracellular Vesicles and PIBF in Embryo-Maternal Immune-Interactions

Pregnancy represents a unique immunological situation. Though paternal antigens expressed by the conceptus are recognized by the immune system of the mother, the immune response does not harm the fetus. Progesterone and a progesterone induced protein; PIBF are important players in re-adjusting the functioning of the maternal immune system during pregnancy. PIBF expressed by peripheral pregnancy lymphocytes, and other cell types, participates in the feto-maternal communication, partly, by mediating the immunological actions of progesterone. Several splice variants of PIBF were identified with different physiological activity. The full length 90 kD PIBF protein plays a role in cell cycle regulation, while shorter splice variants are secreted and act as cytokines. Aberrant production of PIBF isoforms lead to the loss of immune-regulatory functions, resulting in and pregnancy failure. By up regulating Th2 type cytokine production and by down-regulating NK activity, PIBF contributes to the altered attitude of the maternal immune system. Normal pregnancy is characterized by a Th2-dominant cytokine balance, which is partly due to the action of the smaller PIBF isoforms. These bind to a novel form of the IL-4 receptor, and induce increased production of IL-3, IL-4, and IL-10. The communication between the conceptus and the mother is established via extracellular vesicles (EVs). Pre-implantation embryos produce EVs both in vitro, and in vivo. PIBF transported by the EVs from the embryo to maternal lymphocytes induces increased IL-10 production by the latter, this way contributing to the Th2 dominant immune responses described during pregnancy

A word of caution: do not wake sleeping dogs; micrometastases of melanoma suddenly grew after progesterone treatment

Background: Hormonal treatment might affect the immune response to tumor antigens induced in cancer patients who are being vaccinated. Case presentation: A 33 years-old woman was diagnosed with cutaneous melanoma in May 2009. Her melanoma was located in the intermammary sulcus, had a Breslow thickness of 4 mm, a Clark’s level IV, it was ulcerated and highly melanotic. The bilateral sentinel node biopsy was negative. She entered into a randomized Phase II/III clinical study comparing a vaccine composed of irradiated melanoma cells plus BCG plus GM-CSF versus IFN-alpha 2b and she was assigned to the vaccine arm. During the two years treatment she remained disease-free; the final CAT scan being performed in August 2011. Between November and December 2011, her gynecologist treated her with three cycles of 200 mg progesterone/day for ten days, every two weeks, for ovary dysfunction. In November 2011 the patient returned to the Hospital for clinical and imaging evaluation and no evidence of disease was found. At the next visit in March 2012 an ultrasound revealed multiple, large metastases in the liver. A CAT scan confirmed the presence of liver, adrenal glands and spleen metastases. A needle biopsy of a liver lesion revealed metastatic melanoma of similar characteristics to the original tumor. We suggest that progesterone treatment triggered proliferation of so far dormant micrometastases that were controlled during CSF470 vaccine treatment. Conclusion: The use of progesterone in patients with melanoma that are under immunological treatments should be carefully considered, since progesterone could modify the balance of pro-inflammatory and Th1 functions to a regulatory and anti-inflammatory profile of the immune system that could have an impact in tumor progression.Fil: Mordoh, Jose. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tapia, Ivana Jaqueline. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barrio, Maria Marcela. Fundacion Cancer. Centro de Investigaciones Oncologicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

PIBF+ extracellular vesicles from mouse embryos affect IL-10 production by CD8+ cells

Earlier evidence suggests, that the embryo signals to the maternal immune system. Extracellular vesicles (EVs) are produced by all types of cells, and because they transport different kinds of molecules from one cell to the other, they can be considered as means of intercellular communication. The aim of this work was to test, whether the embryo is able to produce sufficient amounts of EVs to alter the function of peripheral lymphocytes. Embryo-derived EVs were identified by their Annexin V biding capacity, and sensitivity to Triton X dependent lysis, using flow cytometry. Transmission electron microscopy was used to detect EVs at the implantation site. Progesterone-induced blocking factor (PIBF) expression in embryo-derived EVs was demonstrated with immuno-electron microscopy. The % of IL-10 + murine lymphocytes was determined by flow cytometry. EVs were present in embryo culture media, but not in empty media. Mouse embryo-derived EVs adhere to the surface of both CD4+ and CD8+ murine peripheral T lymphocytes, partly, via phosphatidylserine binding. The number of IL-10+ murine peripheral CD8+ cells increases in the presence of embryo-derived EVS, and this effect is counteracted by pre-treatment of EVs with an anti-PIBF antibody, suggesting that the embryo communicates with the maternal immune system via EVs

Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation.

During 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

Characterization of mixed lymphocyte reaction blocking antibodies (MLR-Bf) in human pregnancy

BACKGROUND: It is known that during normal pregnancy and after immunotherapy blocking antibodies are developed, these antibodies inhibit mixed lymphocyte reaction and are also anti-mitogenic in nature. Mixed lymphocyte reaction blocking antibodies are specific to the husband's lymphocytes. In the present study an attempt has been made to characterize the mixed lymphocyte reaction blocking antibodies in normal pregnancy and in women with recurrent spontaneous abortion after immunotherapy. METHODS: Serum was obtained from women of different gestational windows of pregnancy (Ist, IInd, IIIrd trimesters and post delivery period of normal pregnancy), recurrent spontaneous aborters from pre and post immunization. Healthy (male and females) controls were screened for the presence of mixed lymphocyte reaction blocking antibodies. The standard mixed lymphocyte reaction technique was used to evaluate the inhibitory effect of serum in the mixed lymphocyte reaction. Each serum was tested for cytotoxic antibodies. Immunoglobulin G and its isotypes were isolated according to the standard protocol. RESULTS: In the present study we have observed that there was significant inhibition of proliferation response when immunoglobulin G from different trimesters of pregnancy were added to one way mixed lymphocyte reaction or to phytohemagglutinin activated lymphocyte proliferation assay. Similar pattern was seen when immunoglobulin G isolated from adequately immunized women with recurrent spontaneous abortion was used. It was further confirmed that amongst all the isotypes of immunoglobulin G, only immunoglobulin G-3 was found to be positive for the inhibitory effect. CONCLUSIONS: Present study indicates that mixed lymphocyte reaction blocking antibodies are immunoglobulin G-3 in nature. It is developed during pregnancy and also after immunotherapy in women with recurrent spontaneous abortion who subsequently have the successful pregnancy

Disseminated Mycobacterium avium complex infection in an immunocompetent pregnant woman

BACKGROUND: Disseminated mycobacterium avium complex (MAC) occurs mainly in immunocompromised hosts, which is associated with abnormal cellular immunity. CASE PRESENTATION: A 26-year-old pregnant woman presented with fever and general weakness. Miliary lung nodules were noted on chest X-ray. Under the impression of miliary tuberculosis, anti-tuberculosis medication was administered. However, the patient was not improved. Further work-up demonstrated MAC in the sputum and placenta. The patient was treated successfully with clarithromycin-based combination regimen. CONCLUSION: This appears to be the first case of disseminated MAC in an otherwise healthy pregnant woman. Clinicians should be alert for the diagnosis of MAC infection in diverse clinical conditions

The immunobiology of cord blood transplantation

Despite significant recent advances in the applicability and outcome following unrelated cord blood transplantation (UCBT), infections remain a major cause of mortality associated with poor immune recovery in the first 6 months after UCBT. Enhanced immune reconstitution not only could improve survival by reduced transplant related mortality, but may also favorably impact on relapse incidence by improved graft-versus-leukemia effects. This review will summarize our current understanding of the biology of immune recovery post-UCBT with an emphasis on adaptive T cell dependent immunity. New efforts to boost immunity will be also highlighted including our own laboratory, where ex vivo T cell expansion is pursued towards adoptive immunotherapy