Postpartum maternal exposure to predator odor alters offspring antipredator behavior, basal HPA axis activity and immunoglobulin levels in adult Brandt's voles.

Predation risk can program offspring behavior, physiology, and fitness through maternal effect, but most studies have mainly focused on this effect during pregnancy; little is known about the effect of postpartum predation risk on offspring's phenotype. Here, we compared the antipredator behaviors of adult offspring (approximately 90 days old) produced by female Brandt's voles (Lasiopodomys brandtii) exposed to one of three treatments: cat odor (CO), rabbit odor (RO), and distilled water (DW) for 60 min daily from postpartum day 1-18. Basal levels of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT), hypothalamic corticotrophin releasing hormone (CRH), as well as spleen immunoglobulins (IgA, IgM, and IgG) were also measured. Our data showed that the offspring of CO-exposed mothers displayed less head-out behavior to acute 15-min CO exposure, and female offspring showed more freezing behavior. CO offspring showed significantly lower basal ACTH and CORT levels than the RO and DW offspring. Additionally, female but not male CO offspring had higher hypothalamic CRH expression and spleen IgG levels than controls, showing a sex-specific effect. These findings demonstrate that postpartum maternal predator risk exposure promotes a passive-avoidant response to these cues in adult offspring, showing a cross-generational maternal effect of postpartum predation risk. Further, these changes may be associated with alterations in the hypothalamic-pituitary-adrenal axis and immune function.

Preliminary Evidence of Endotoxin Tolerance in Dairy Cows during the Transition Period.

The blastogenic response of bovine peripheral blood mononuclear cells (PBMCs) to lipopolysaccharides (LPS) has been investigated for a long time in our laboratories. In particular, a possible correlation between the blastogenic response to LPS and the disease resistance of dairy cows has been suggested in previous studies. Isolated PBMCs from eight cows at three different time points during the transition period (T0 = 15 days before calving; T1 = 7 days post-calving; T2 = 21 days post-calving) were cultured in the presence or absence of LPS, and the blastogenic response was assayed 72 h after in vitro stimulation. Moreover, the gene expression of proinflammatory cytokines and kynurenine pathway molecules was investigated by real-time RT-PCR on both unstimulated and stimulated PBMCs. The cows were retrospectively divided into healthy and diseased, based on the development of peripartum diseases (subclinical ketosis and placenta retention). The comparison between healthy and diseased cows suggested that healthy animals seemed to better control the response to LPS. On the contrary, diseased animals showed a much higher inflammatory response to LPS. Moreover, cows were retrospectively classified as high and low responders based on the in vitro proliferative response of PBMCs to LPS, using the median value as a threshold. Unstimulated PBMCs of low responders showed higher expression of the proinflammatory cytokines Interleukin 1-ß (IL-1ß), Interleukin 6 (IL-6) and Tumor Necrosis Factor-α (TNF-α), compared to high responders. Our preliminary data suggest that, during the peripartum period, high responders seem to be more tolerant to endotoxins and develop a lower inflammatory response to different stressors. Instead, low responders could be more prone to the development of unwanted inflammatory conditions in response to mild/moderate stressors.

Pregnancy in Patients With AQP4-Ab, MOG-Ab, or Double-Negative Neuromyelitis Optica Disorder.

OBJECTIVE: To analyze the effects of pregnancy on neuromyelitis optica spectrum disorder (NMOSD) according to patients' serostatus and immunosuppressive therapy (IST). METHODS: We performed a retrospective multicenter international study on patients with NMOSD. Patients were tested for aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). Informative pregnancies were reported when NMOSD onset occurred before or during pregnancy or up to 12 months postpartum. The mean annualized relapse rate (ARR) was calculated for the 12 months before conception, for each trimester of pregnancy, and postpartum. Events such as miscarriage, abortion, and preeclampsia were reported. IST was considered if taken in the 3 months before or during pregnancy. RESULTS: We included 89 pregnancies (46 with AQP4-Ab, 30 with MOG-Ab, and 13 without either Ab) in 58 patients with NMOSD. Compared to the prepregnancy period, the ARR was lower during pregnancy in each serostatus group and higher during the postpartum period in patients with AQP4-Ab (p < 0.01). Forty-eight percent (n = 31) of pregnancies occurred during IST and these patients presented fewer relapses during pregnancy and the 12 months postpartum than untreated patients (26% vs 53%, p = 0.04). Miscarriages occurred in 10 (11%) pregnancies, and were mainly in patients with AQP4-Ab (with or without IST) and a previous history of miscarriage. Preeclampsia was reported in 2 (2%) patients who were AQP4-Ab-positive. CONCLUSION: We found a rebound in the ARR during the first postpartum trimester that was higher than the prepregnancy period only in AQP4-Ab-positive patients. Taking IST just before or during pregnancy reduces the risk of relapses in these conditions.

Blood leukocyte composition and function in periparturient ewes kept on different dietary magnesium supply.

BACKGROUND: Transition period (TP) is characterised by physiological and metabolic changes contributing to immunodysregulation. Since knowledge about this period in sheep is scarce, we analysed changes in selected immune variables during the TP in ewes and whether dietary magnesium (Mg) supplementation could modulate these immune variables. Pregnant ewes (2nd and 3rd lactation) were divided into a control group (CONT, n = 9) and a Mg group (MAG, n = 10) supplemented with Mg oxide resulting in a daily Mg intake of approximately 0.30 and 0.38% (MAG) of dry matter during ante- (a.p.) and post-partum (p.p.) periods, respectively. Blood samples were collected between days (d) 30 a.p. and d 30 p.p.. Whole blood neutrophil phagocytic activity, monocyte subset (classical cM, intermediate intM, non-classical ncM) composition and the proliferative capacity of lymphocytes were determined flow cytometrically. At d 14 a.p., all ewes were vaccinated against Mycobacterium avium subsp. paratuberculosis (MAP). RESULTS: Both groups showed a sharp increase in the total leukocyte counts (TLC) and neutrophil counts (P < 0.0001), at d 1 p.p., while, monocytes and their subpopulations displayed the highest values at d 30 p.p. (P ≤ 0.05). At d 1 p.p. the neutrophil phagocytic activity was higher (P < 0.05) in MAG ewes. Throughout the TP, the proliferative response of CD4+ cells was significantly higher in the MAG group (P < 0.05). Ewes in both groups responded with an increase in the TLC, neutrophil numbers (P ≤ 0.05) and ncM (P < 0.001) 24 h post vaccination, whereas monocytes and cM dropped in numbers (P ≤ 0.05). Numbers of intM only increased in MAG ewes (P < 0.05), whereas lymphocyte numbers decreased (P < 0.01). Mg supplementation did not affect the significant increase in MAP-specific antibodies at d 7 and 21 post vaccination. Total Mg and Ca serum levels did not show any differences between the two groups. CONCLUSION: Whereas TP-associated fluctuations in blood leukocyte numbers are not influenced by Mg supplementation, neutrophil phagocytic activity, the proliferative capacity of CD4+ cells and the cellular response within 24 h after a vaccination are subject to modulation.

Impact de la grossesse sur le psoriasis.

During pregnancy there is spontaneous improvement in various inflammatory diseases, including psoriasis for the majority of women. Hormonal changes during pregnancy may play a role in improving psoriasis by promoting a state of transient immune tolerance, promoting a TH2-type response, and lowering the inflammatory cascades of psoriasis. It is more the ratio of estrogens to progesterone than the respective relative levels of the circulating hormones themselves that may improve psoriasis. There is a risk of psoriasis flare in the first few months postpartum. Breastfeeding seems to have less influence on the natural history of skin lesions.

Autoimmune Hepatitis: Tolerogenic Immunological State During Pregnancy and Immune Escape in Post-partum.

The maternal immune system engages in a fine balancing act during pregnancy by simultaneously maintaining immune tolerance to the fetus and immune responses to protect against invading organisms. Pregnancy is an intricately orchestrated process where effector immune cells with fetal specificity are selectively silenced. This requires a sustained immune suppressive state not only by expansion of maternal Foxp3+ regulatory T cells (Tregs) but also by leaning the immune clock toward a Th2 dominant arm. The fetus, known as a semi-allograft or temporary-self, leads to remission of autoimmune hepatitis during pregnancy. However, this tolerogenic immune state reverts back to a Th1 dominant arm, resulting in post-partum flare of AIH. Various hormones play a significant role in endocrine-immune axis during pregnancy. The placenta functions as a barrier between the maternal immune system and the fetus also plays a pivotal role in creating a tolerogenic environment during pregnancy. We review the evidence of immune tolerance during pregnancy and immune escape at post-partum period, focusing on patients with autoimmune hepatitis.

Characterization of immunological, biochemical and inflammatory response of clinical and subclinical endometritis in ewes in the subtropics.

Pluriparus Ossimi (n = 50) ewes were used to investigate the immune profile of the affected ewes to accurately diagnose clinical and subclinical endometritis and associations with biochemical variables. Ewes were slaughtered and animals were classified into control (no fertility problems), subclinical endometritis (SCE) and clinical endometritis (CE) groups based on pre-slaughter determinations of conception failure. Serum was collected from ewes to estimate concentrations of pro-inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) as well as nitric oxide (NO) concentration. The results from immunological evaluations indicated there were greater (P < 0.001) serum concentrations of IL-6, IL-8, TNF-α and NO in ewes classified with SCE and CE as compared to ewes of the control group. Furthermore, values for concentrations of TNF-α were positively correlated with IL-6 and IL-8 concentrations in ewes of the SCE and CE groups. In ewes classified with CE and SCE there were greater (P < 0.01) concentrations of blood glucose, ALT, AST, urea and creatinine than in ewes of the control group. It is concluded that serum pro-inflammatory cytokines IL-6, IL-8, and TNF-α are diagnostic markers for CE and SCE in ewes and serve as a criterion for different inflammatory complications in ewes classified as having CE or SCE.

Evidence of macrophage modulation in the mouse pubic symphysis remodeling during the end of first pregnancy and postpartum.

In mouse pregnancy, pubic symphysis (PS) remodels into an elastic interpubic ligament (IpL) in a temporally regulated process to provide safe delivery. It restores at postpartum to assure reproductive tract homeostasis. Recently, macrophage localization in the IpL and dynamic changes in the expression of inflammatory mediators observed from the end of pregnancy (D18, D19) to early days postpartum (1dpp, 3dpp) highlighted the necessity of the identification of the key molecules involved in innate immune processes in PS remodeling. Therefore, this study uses morphological and high-sensitivity molecular techniques to identify both macrophage association with extracellular matrix (ECM) remodeling and the immunological processes involved in PS changes from D18 to 3dpp. Results showed macrophage association with active gelatinases and ECM components and 25 differentially expressed genes (DEGs) related to macrophage activities in interpubic tissues from D18 to 3dpp. Additionally, microarray and proteomic analysis showed a significant association of interpubic tissue DEGs with complement system activation and differentially expressed proteins (DEPs) with phagocytosis, highlighting the involvement of macrophage-related activities in mouse PS remodeling. Therefore, the findings suggest that PS ECM remodeling is associated with evidence of macrophage modulation that ensures both IpL relaxation and fast PS recovery postpartum for first labor.

[Immune-inflammatory and autoimmune mechanisms in postpartum depression].

Postpartum depression is a debilitating mental disorder with a high prevalence, usually related with a past psychiatric history of major depressive disorder, postpartum depression, bipolar disorder, premenstrual syndrome (PMS), and perinatal depressive symptoms during gestation. However, the existing literature does not sufficiently elucidate the pathophysiology of this clinical entity which appears in such a crucial period of woman's life. This review aims to search the available data regarding the involvement of immunological and autoimmune mechanisms in its onset. A literature review was conducted using web-based search engines provided by PubMed (for Medline database) and Google Scholar. Manuscripts in English and Greek language were included for the period 19902017. Nowadays, a large body of evidence indicates that depressive disorders are accompanied by activated neuro-immune, neuro-oxidative and neuro-nitrosative stress (IO&NS) pathways. However, clinical research regarding the biological mechanisms associated with PPD is a tough challenge as pregnancy and puerperium are periods of adaptive changes in pregnant women by definition. Two of the systems that have been studied as potentially contributing to the onset of PPD are: the activation of the Inflammatory Response System (IRS) and the deregulation of the Hypothalamic-PituitaryAdrenal axis (HPA). Controversial data indicate dysregulation of cytokines and other inflammatory agents in patients with PPD, as well as, a close correlation of immune-inflammatory mechanisms and kynurenine pathway. PPD has been closely associated with autoimmune diseases. It is notable that this entity shares many common traits with autoimmune diseases such as the genetic susceptibility, family history, the high correlation with other autoimmune diseases, clinical exacerbations and remissions, women's superiority in prevalence, and the possible re-occurrence during a future pregnancy. These facts suggest that the typical postpartum flare pattern, and other clinical characteristics, point towards an autoimmune etiology for PPD. There are indications that immune-inflammatory and autoimmune mechanisms may be the key to deciphering the complex pathophysiological pathways associated with the onset of PPD. Clinical studies have been insufficient to make clear the causative correlations of the underlying mechanisms involved. Future research could focus on the immune-inflammatory processes associated with the onset of the disease, as well as on potential biomarkers for an early diagnosis and an effective treatment of PPD.

Associations between circulating levels of natural antibodies, total serum immunoglobulins, and polymorphonuclear leukocyte function in early postpartum dairy cows.

The objective of this study was to investigate the associations between natural antibodies (NAbs) and total serum immunoglobulins (Igs) concentrations (both from IgG and IgM isotypes), with variables of polymorphonuclear leukocytes (PMN) function of dairy cows in the early postpartum period. Seventy-five healthy postpartum dairy cows at 2 ± 1 days in milk were enrolled in a cross-sectional study. Natural and total antibodies in serum samples were measured by ELISA. Flow cytometry was used to determine the phagocytosis and oxidative burst capacities of PMN and the quantification of the adhesion molecule l-selectin. Leukocyte count and differentials, and serum haptoglobin were also measured. A positive correlation between NAbsIgM and total serum IgM and between NAbsIgM and NAbsIgG were found. Before performing the associations between circulating Igs concentrations and PMN function variables, cows were categorized into having low, medium or high circulating antibodies based on their NAbs and total Igs serum concentrations. None of the PMN variables assessed differed between low, medium, and high cows for both NAbsIgM and NAbsIgG. While associations between PMNs function and total IgG were not observed, some associations between total IgM concentrations and PMN activity were found. Cows with high serum IgM had greater phagocytic activity compared to cows in the low IgM group. Finally, the proportion of PMN that performed oxidative burst and PMN surface expression of l-selectin intensity was greater in high total IgM group when compared to medium and low groups. In conclusion, association between NAbs, and PMN activity variables were not observed, but total serum IgM was associated to some PMN function variables in early post-partum dairy cows.

Psychiatric disorders and changes in immune response in labor and postpartum.

Women may present with psychiatric disorders during pregnancy, normal labor, following delivery by caesarean section, or in the postpartum period. The accumulating evidence suggests that these disorders may be due to changes in immune responses. During pregnancy complications such as the prolongation of cervical ripening or descent, placental abruption, premature labor, and preeclampsia increase the risk of postpartum psychiatric disorders. Women may exhibit depression and postpartum psychosis following either normal birth or caesarean section. Since psychiatric disorders like schizophrenia, major depression, and bipolar disorder are associated with both alterations in the immune response and changes in immune cell subpopulations, in this study we have chosen to examine whether the psychiatric disorders in women during labor or postpartum also lead to aberrant immune responses.

Low frequency of flares during pregnancy and post-partum in stable lupus patients.

BACKGROUND: Lupus patients are at risk for pregnancy loss, and it has been generally accepted that women with SLE should have low disease activity prior to conception. However, there are conflicting results regarding the effect of pregnancy on SLE flares. This study aims to identify predictors of flares during and after pregnancy in SLE patients with inactive or stable disease activity during the first trimester and to characterize and estimate the frequency of post-partum flares in these patients. METHODS: SLE patients in the multicenter, prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study were evaluated for flares during and after pregnancy using the SELENA-SLEDAI Flare Index. Flares during pregnancy were assessed in all 384 patients and post-partum flares in 234 patients with study visits 2-6 months post-partum. Logistic regression models were fit to the data to identify independent risk factors for flare. RESULTS: During pregnancy, 20.8% of patients had mild/moderate flares and 6.25% had severe. Post-partum, 27.7% of patients had mild/moderate flares and 1.7% had severe. The mild flares rarely required treatment. Younger age, low C4 and higher PGA at baseline were independently associated with higher risk of having at least one mild/moderate or severe flare during pregnancy. Older patients were at decreased risk of flare, as well as those with quiescent disease at baseline. No variables evaluated at baseline or the visit most proximal to delivery was significantly associated with risk of flare post-partum. Medications were not associated with flare during or after pregnancy. CONCLUSION: In patients with inactive or stable mild disease activity at the time of conception, lupus disease flares during and after pregnancy are typically mild and occur at similar rates. Flares during pregnancy are predicted by the patients' age and clinical and serological activity at baseline.

Adaptive immunity in the postpartum uterus: Potential use of vaccines to control metritis.

After parturition, dairy cows rely on an effective innate immune response, through the actions of neutrophils, macrophages, and antimicrobial peptides, to clear the uterus from pathogenic bacteria, such as E. coli, Bacteroides spp, F. necrophorum and T. pyogenes. However, the role of adaptive immunity in the postpartum uterus is less understood. In this review, we explore concepts of mucosal adaptive immunity and discuss recent findings regarding the efficacy of vaccines to reduce metritis in dairy cows. Areas of lymphocytic aggregates are seen throughout the bovine reproductive tract after parturition, but it is unknown if their development is influenced by previous exposure to pathogens or other intrinsic factors. Through the actions of Treg cells and γδ T cells, the uterus is an immune-tolerant environment during pregnancy. After parturition, the dynamics in the endometrial and circulating lymphocytic populations differ among cows that develop uterine diseases and healthy counterparts. However, the functionality of those cells has not yet been determined. It has been hypothesized that cows that fail to switch their uterine environment from an anti-inflammatory state prior to parturition to a pro-inflammatory state after calving are more susceptible to uterine infections. Given the nature of metritis related pathogens and the importance of innate immunity to uterine defense mechanisms, we speculate that an adaptive immunity biased towards a Th1/Th17 cellular response will provide best protection against uterine infections. Few studies have evaluated the efficacy of immunization in reducing the incidence of metritis in dairy cows revealing inconsistent findings.

Zika Virus Alters the Viscosity and Cytokines Profile in Human Colostrum.

The resurgence of cases of Zika virus (ZIKV) infection, accompanied by epidemic of microcephaly in Brazil, has aroused worldwide interest in understanding the biological mechanisms of the virus that allow patient management and the viral dissemination control. Colostrum and human milk are possible sources of virus spread. Therefore, the objective of this study was to analyze the repercussions of ZIKV infection on rheological parameters and inflammatory cytokines of colostrum. The prospective cohort study included 40 puerperal donors of colostrum, divided into 2 groups: control (without ZIKV infection, n = 20) and a group infected with ZIKV during the gestational period (n = 20). Analyses were performed for the detection of ZIKV by polymerase chain reaction (PCR). In addition to obtaining the rheological parameters and quantification of IL-10 and IL-6 cytokines by flow cytometry, ZIKV and other flaviviruses were not detected in colostrum. However, maternal infection reflected increased viscosity, decreased levels of IL-10, and elevated levels of IL-6. The higher viscosity may represent a mechanical barrier that hinders the spread of the virus. The lower levels of anti-inflammatory mediators and higher inflammatory cytokines may possibly alter the viscosity, and it seems the higher viscosity represents a possible mechanism of adaptation of breastfeeding against a response to ZIKV.

Exacerbations of autoimmune diseases during pregnancy and postpartum.

Autoimmune diseases represent a complex heterogeneous group of disorders that occur as a results of immune homeostasis dysregulation and loss of self-tolerance. Interestingly, more than 80% of the cases are found among women at reproductive age. Normal pregnancy is associated with remarkable changes in the immune and endocrine signaling required to tolerate and support the development and survival of the placenta and the semi-allogenic fetus in the hostile maternal immune system environment. Gravidity and postpartum represent an extremely challenge period, and likewise the general population, women suffering from autoimmune disorders attempt pregnancy. Effective preconception counseling and subsequent gestation and postpartum follow-up are crucial for improving mother and child outcomes. This comprehensive review provides information about the different pathways modulating autoimmune diseases activity and severity, such as the influence hormones, microbiome, infections, vaccines, among others, as well as updated recommendations were needed, in order to offer those women better medical care and life quality.

Recurrent post-partum rhombencephalitis associated with anti-centromere antibody: a case report.

BACKGROUND: Rhombencephalitis (RE) is a serious condition of the brain with multiple etiologies. We report a unique case of recurrent, postpartum RE that is associated with positive anti-centromere antibody (ACA). A discussion of the case, current literature on autoimmune RE and related autoantibodies are reviewed. CASE PRESENTATION: A healthy 33-year-old Caucasian patient (gravida 2, para 2) had two episodes of progressive focal neurological deficits during postpartum periods. Signs and symptoms included right-sided dysmetria, adiadochokinesia, weakness, ataxia, and photophobia. MRI revealed rhombencephalitis involving the mesencephalon of the brainstem. Extensive and comprehensive investigations using blood and cerebrospinal fluid (CSF) were consistently positive only for ACA. The first episode was successfully treated with empiric antimicrobial agents and steroid. Given the negative infectious work up with the prior episode and the nearly identical clinical presentations, the second episode was treated with corticosteroid only. This led to complete resolution of her symptoms and reversal of the brain magnetic resonance imaging (MRI) lesions. CONCLUSION: To the author's knowledge, this is the first report of a primary autoimmune RE during postpartum period that is associated with ACA. Immunologic causes should be considered early with any encephalitis. Given the risk of recurrence, relapse, and neurologic deterioration, regular monitoring is recommended, especially for female patients of child-bearing age. Consistent with the current literature on autoimmune RE, steroid seems to be an effective treatment for ACA-associated RE.

Sheep and goats raised in mixed flocks have diverse immune status around parturition.

Several physiological and metabolic changes take place in dairy ruminants around parturition (late pregnancy, parturition, and early lactation). Dairy species are genetically selected for their higher milk production compared with non-dairy species. This fact causes a constant stress that impairs the immune status of the animal, with consequences for its welfare and performance. In the present study, we assessed the immune status of high-yield dairy sheep and goats by quantifying IgG and IgM concentrations, as well as chitotriosidase (ChT) and complement system [total complement system (TC) and alternative complement pathway (AC)] activity in blood plasma around parturition. We also measured IgG and IgM concentrations and ChT activity in colostrum and milk during the first 40 d postpartum. The lowest blood IgG concentration was at parturition in both species. We detected no differences in blood IgG concentrations between species. Blood IgM concentrations were constant in both species throughout the study period. However, blood IgM concentrations were greater in sheep than in goats. Blood ChT activity was greater in goats than in sheep, and both species showed constant activity of this enzyme throughout the study period. We observed no differences in complement system (TC and AC) activity between sheep and goats. In addition, both TC and AC activity were constant in both species throughout the experiment. In general, IgG and IgM concentrations were greater in sheep colostrum than in goat colostrum, but these differences disappeared after d 4 (IgG) and d 3 (IgM) postpartum. In both species, the highest IgG and IgM concentrations were measured in colostrum, gradually decreasing during the first days postpartum. Chitotriosidase activity decreased in both species from colostrum to milk, although goats always showed greater ChT activity than sheep. Both sheep and goats seemed to be more susceptible to infectious diseases around parturition. As well, goats showed greater ChT activity in blood, colostrum, and milk than sheep. This fact may give these animals additional protection against parasite and fungal infections.

PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density.

Post-partum breast cancer patients, or breast cancer patients diagnosed within 10 years of last childbirth, are ~3-5 times more likely to develop metastasis in comparison to non-post-partum, or nulliparous, patients. Additionally, post-partum patients have increased tumor-associated lymphatic vessels and LN involvement, including when controlled for size of the primary tumor. In pre-clinical, immune-competent, mouse mammary tumor models of post-partum breast cancer (PPBC), tumor growth and lymphogenous tumor cell spread occur more rapidly in post-partum hosts. Here we report on PD-L1 expression by lymphatic endothelial cells and CD11b+ cells in the microenvironment of post-partum tumors, which is accompanied by an increase in PD-1 expression by T cells. Additionally, we observed increases in PD-L1 and PD-1 in whole mammary tissues during post-partum mammary gland involution; a known driver of post-partum tumor growth, invasion, and metastasis in pre-clinical models. Importantly, implantation of murine mammary tumor cells during post-partum mammary gland involution elicits a CD8+ T cell population that expresses both the co-inhibitory receptors PD-1 and Lag-3. However, upon anti-PD-1 treatment, during post-partum mammary gland involution, the involution-initiated promotional effects on tumor growth are reversed and the PD-1, Lag-3 double positive population disappears. Consequently, we observed an expansion of poly-functional CD8+ T cells that produced both IFNγ and TNFα. Finally, lymphatic vessel frequency decreased significantly following anti-PD-1 suggesting that anti-PD-1/PD-L1 targeted therapies may have efficacy in reducing tumor growth and dissemination in post-partum breast cancer patients.

Immune status during postpartum, peri-implantation and early pregnancy in cattle: An updated view.

Throughout the estrous cycle the mammalian endometrium undergoes morphological and functional changes that are essential for the establishment of pregnancy and proper ovarian and uterine functions. Among these changes, the most important are alterations in both inter- and intracellular signalling molecules, many of which modulate immune processes. In the endometrial tissue there are local innate (nonspecific) and adaptive (specific/acquired) response mechanisms which vary because of the endocrine status during the estrous cycle, pregnancy and postpartum period. Endometrial cells have responses that support the immune system by producing pro-inflammatory factors such as cytokines, sensors, effector molecules and chemokines. This response is important during gestation, pregnancy, and fetal growth, as well as in preventing infection, and immuno-rejection of the semi-allogeneic embryo. In dairy cows, both before and immediately after calving, there are marked changes in the values for hormonal and metabolic variables and the immune status is impaired. Thus, in several studies there has been assessment of the physiological and/or abnormal maternal immune changes and possible effects on dairy cow reproductive performance. The objective with this review is to summarize the novel information about the immune mechanisms involved during the postpartum period, subsequent peri-implantation period and pregnancy in dairy cows, and the possible effects on reproductive performance. This information provides for an enhanced understanding of the local and systemic immune responses associated with the metabolic and hormonal status of dairy cows, and alterations in the immune system of high producing cows and the possible effects on subsequent fertility.