Regulační T-lymfocyty (Treg) zastávají důležitou úlohu v imunitním systému, předcházejí autoimunitním onemocněním, udržují imunitní homeostázu a modulují imunitní odpověď pri infekci. S rostoucím povědomí o této tolerogenní subpopulaci zjišťujeme, zeje také nepostrádatelná v úspěšném průběhu těhotenství, kde spoluvytvári mateřskou toleranci vůči plodu. Během celého těhotenství je na Treg lymfocyty velmi bohatá tkáň, která se nachází na rozhraní matky a plodu, tzv. deciduální tkáň. Výrazná dynamičnost Treg subpopulace byla také zaznamenána ''' .^ettfemí krvi těhotných žen s nejvyšším počtem buněk ve dmhém trimestm těhotenství. Tyto změny jsou u atopických pacientek potlačeny a mohou prispívat ke komplikacím, napri'klad předčasnému porodu. Do budoucna má model Treg T-lymfocytů velký terapeutický potenciál v léčbě některých pomch reprodukce.
Regulatory T-cells (Treg) have important modulatory roles in the immune system, to prevent autoimmune disease, to maintain immune ho - meostasis and to modulate immune responses during infection. There is a steady increase in the knowledge of tolerogenic subpopulation and we detect that Treg cells are indispensable for successful progress of pregnancy because of their ability to jointly participate on the maternal tolerance of the fetus. Treg cells are very enriched at the fetal-maternal interface, in the decidua tissue . The number of Treg cells is also in - creased in the circulation of pregnant women, reaching the peak in the second trimester of pregnancy. These changes are suppressed in atopic women and could contribute to the complications such as preterm birth. Treg cells reveal a great therapeutic potential for treatment of some pathologies of reproduction.
- Keywords
- T-regulační lymfocyty,
- MeSH
- Lymphocyte Activation MeSH
- Asthma MeSH
- Cell Physiological Phenomena MeSH
- Immune System Phenomena MeSH
- Immune Tolerance MeSH
- Humans MeSH
- T-Lymphocytes physiology immunology MeSH
- Pregnancy MeSH
- Pregnancy Trimesters MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
Diabetes 1. typu (DM1) vzniká jako následek autoimunitní destrukce beta buněk pankreatu. Vliv diabetu na celkový výsledek těhotenství je poměrně dobře prostudován. Mnohem méně se toho však ví o vlivu diabetu matky na vyvíjející se imunitní systém plodu. Riziko rozvoje DM1 u dětí diabetických matek (pokud onemocněly před těhotenstvím) je nižší než např. u dětí diabetických otců. Tato diskrepance podporuje teorii, že by mohlo docházet k určitému navození imunotolerance u dětí DM1 matek. Z tohoto důvodu jsme si pro náš výzkum vybrali T regulační buňky (Tregs), které hrají důležitou roli v imunoregulaci a patogenezi mnoha autoimunitních onemocnění. Studie Tregs pupečníkové krve DM1 matek jsou navíc ojedinělé. Pomocí průtokové cytometrie jsme analyzovali zastoupení Tregs (definovaných jako CD45+ CD3+ CD4+ CD25+ CD127(low/-)) ve vzorcích pupečníkové krve od 17 matek s DM1, 17 s gestačním diabetem a 42 zdravých kontrol. Signifikantní rozdíl jsme nalezli jen v zastoupení Tregs z Th lymfocytů, kde v pupečníkové krvi zdravých matek činil tento poměr 9,25 % a u matek s DM1 6,73 % (p=0,043). Ostatní rozdíly nedosáhly signifikance. Pokud tedy dochází k navození specifické imunotolerance, je tato patrně podmíněna jinak než změnou počtu Tregs. Pokračujeme proto ve funkční analýze Tregs s cílem nalézt vysvětlení pro nižší výskyt diabetu u dětí DM1 matek ve srovnání s ostatními prvostupňovými příbuznými DM1 pacientů. Pochopení tohoto jevu by mohlo přispět např. i k vytvoření imunointervenční terapie DM1.
Type 1 diabetes (T1D) develops due to autoimmune pancreatic beta cells destruction. The effect of diabetes on pregnancy outcome is well documented. However, much less is known about the effect of maternal diabetes on the developing foetal immune system. The risk of T1D development in a child of T1D mother who was diagnosed prior pregnancy is lower than e.g. in a child of T1D father. This discrepancy supports the theory that there is some immunoregulatory influence on her baby. For this reason we decided to study T regulatory cells (Tregs) which are important in immunoregulation and for autoimmune diseases pathogenesis. Moreover Tregs cord blood (CB) studies of T1D mothers are limited. Tregs defined as CD45+ CD3+ CD4+ CD25+ CD127(low/-) in CB samples were investigated in our study by flow cytometry and 17 T1D mothers, 17 gestation diabetes mothers and 42 healthy controls were enrolled. We found just that CB from babies of T1D mothers contained 6,73 % Tregs/total Th-lymfocytes in comparison to 9,25 % in controls (p = 0,043). Other differences were not significant. If an establishment of specific immunological tolerance in foetus of T1D mother really exists, it seems to be rather due to other factors than just to changes in Tregs count (which was moreover found to be decreased). We are currently focused on explanation why children of T1D mothers suffer from diabetes less frequently than other first degree relatives by using functional analysis of Tregs. Insights in to this phenomenon would be useful e.g. for construction of T1D immunointervention therapy.
- Keywords
- diabetes 1. typu, imunotolerance,
- MeSH
- Autoantibodies blood MeSH
- Self Tolerance immunology MeSH
- Diabetes Mellitus, Type 1 immunology MeSH
- Adult MeSH
- Fetal Blood immunology MeSH
- Financing, Organized MeSH
- Diabetes, Gestational immunology MeSH
- Humans MeSH
- Maternal-Fetal Exchange MeSH
- Cordocentesis MeSH
- Fetus immunology MeSH
- Flow Cytometry MeSH
- T-Lymphocytes, Regulatory immunology MeSH
- Case-Control Studies MeSH
- Pregnancy in Diabetics immunology MeSH
- Pregnancy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
Regulační T-lymfocyty jsou CD4+ Foxp3+ T-lymfocyty, které in vivo dominantně suprimují imunitní odpověď. Naše snaha porozumět dominantní toleranci navozené v imunitním systému pomocí regulačních T-lymfocytů je příslibem do budoucna při přípravě nových intervenčních terapií u pacientů trpících různými formami alergií a autoimunitních onemocnění jak na buněčné, tak i na molekulární úrovni. Regulační T-lymfocyty jsou rovněž mimořádně efektivní při supresi aloimunity v modelech odvržení štěpu a orgánové transplantace. Tyto nové terapeutické možnosti využití regulačních T-lymfocytů se otevírají na základě jejich intenzivního biologického výzkumu provázeného preklinickým testováním jejich účinků. V tomto přehledu se pokusíme o krátký souhrn nových terapií využívajících imunologických vlastností regulačních T-lymfocytů, jejichž hlavním cílem je maximální benefit při zachování minimálních rizik.
Regulatory T cells (Tregs) are CD4+ Fopx3+ T cells that suppress immune responses in a dominant manner in vivo. In the same time our efforts to understand tolerance mechanism mediated by Tregs at the cellular and molecular levels holds the promise to establish novel immune intervention therapies in patients with allergy or autoimmunity. They have been also shown to be effective in suppressing alloimunity in models of graft-versus-host disease and organ transplantation. It is now time to dissect what is actual impact of Tregs in such a therapeutic context. Building on extensive research in Treg biology and preclinical testing of therapeutic efficacy, we are now at the point of evaluating safety and efficacy of Treg therapy in humans. This review focuses on developing therapy for autoimmune diseases using CD4+ Foxp3+ Tregs, with an emphasis on the studies with principal aim to maximize the benefits while overcoming the challenges and risks of Treg cell therapy.
- MeSH
- Cyclic AMP physiology immunology MeSH
- CTLA-4 Antigen immunology MeSH
- Autoimmunity immunology MeSH
- CD4-Positive T-Lymphocytes immunology MeSH
- Forkhead Transcription Factors immunology MeSH
- Immune System Phenomena physiology immunology MeSH
- Immune System immunology MeSH
- Immunosuppression Therapy MeSH
- Humans MeSH
- Maternal-Fetal Exchange immunology MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Prostaglandins E biosynthesis MeSH
- T-Lymphocytes, Regulatory * immunology metabolism pathology MeSH
- Graft Rejection immunology MeSH
- Arthritis, Rheumatoid immunology physiopathology MeSH
- Immunologic Deficiency Syndromes physiopathology MeSH
- Pregnancy MeSH
- Thymus Gland physiology immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
Pomocné T-lymfocyty zásadním způsobem ovlivňují lidskou reprodukci. Práce přináší současný pohled na funkci a interakci Th-lymfocytů v normální a patologické graviditě , zformulovaný do tzv. Th1/Th2/Th17/T-reg paradigmatu. Analyzuje současné možnosti imunomodulační léč by poruch plodnosti z hlediska ovlivnění počtu a funkcí Th-lymfocytů.
T-helper cells significantly affect human reproduction. Current work provides a contemporary preview on the Th cell functions a nd interacti ons in normal and pathological pregnancies from the view of the Th1/Th2/Th17/T-reg paradigm. We discuss actual possibilities of fertility disorders treatment from the perspective of immuno-modulation of Th cell counts and functions.
- Keywords
- nitrožilní intralipidy,
- MeSH
- Aspirin administration & dosage therapeutic use MeSH
- Th17 Cells physiology immunology drug effects MeSH
- CD4-Positive T-Lymphocytes physiology immunology drug effects MeSH
- Embryonic Development immunology MeSH
- Glucocorticoids administration & dosage therapeutic use MeSH
- Heparin, Low-Molecular-Weight administration & dosage therapeutic use MeSH
- Histocompatibility, Maternal-Fetal immunology MeSH
- Adrenal Cortex Hormones administration & dosage therapeutic use MeSH
- Embryo Implantation immunology drug effects MeSH
- Immunization MeSH
- Immunotherapy methods MeSH
- Immunoglobulins, Intravenous administration & dosage therapeutic use MeSH
- Pregnancy Complications * immunology MeSH
- Condoms adverse effects MeSH
- Humans MeSH
- Premature Birth immunology prevention & control therapy MeSH
- Progesterone administration & dosage therapeutic use MeSH
- T-Lymphocytes, Regulatory physiology immunology drug effects MeSH
- Abortion, Spontaneous drug therapy immunology prevention & control therapy MeSH
- T-Lymphocytes, Helper-Inducer physiology immunology drug effects MeSH
- T-Lymphocytes * physiology immunology drug effects MeSH
- Pregnancy * immunology MeSH
- Th1 Cells physiology immunology drug effects MeSH
- Th2 Cells physiology immunology drug effects MeSH
- Infertility, Female immunology therapy MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Pregnancy * immunology MeSH
- Female MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
T regulační lymfocyty patří do skupiny T lymfocytů, které tlumí imunitní funkce organismu. Hrají důležitou roli v imunitní toleranci plodu v těhotenství, během kterého dochází ke změně jejich počtu v periferní krvi. Existuje již několik studií, které se zabývaly hladinou T regulačních lymfocytů v jednotlivých trimestrech těhotenství, ne však vždy se stejným výsledkem. Cílem této studie bylo zjistit procentuální zastoupení T regulačních lymfocytů během jednotlivých trimestrů, porovnat výsledky s některými již proběhlými studiemi a zjistit, zda má hladina T re-gulačních lymfocytů souvislost s preeklampsií, hypertenzí anebo potratem.
T regulatory lymphocytes belong to group of T-lymphocytes which inhibit immune function of organism. T regulatory lymphocytes play im-portant role in immune tolerance of the fetus during pregnancy, during which their number in peripheral blood is changing. Studies on level of T regulatory lymphocytes in several trimesters of pregnancy exist, however the results differ. The goal of this study was to define percentual representation of T regulatory lymphocytes during each trimester, compare results with some existing studies and define whether level of T re-gulatory lymphocytes has impact on pre-eclampsia, hypertension or abortion.
Cíl studie: Popsat úlohu T-regulačních lymfocytů v patogenezi předčasného porodu. Název a sídlo pracoviště: Gynekologicko-porodnická klinika 1. LF UK a VFN, Praha. Metodika: T-regulační lymfocyty modulují imunitní systém, udržují toleranci vůči vlastním antigenům, a předcházejí tak autoimunitním onemocněním. Vzhledem k těmto vlastnostem je stále více zkoumán jejich vliv na těhotenství, kdy je vlivem tzv. fetomaternálního crosstalku mateřská imunita v kontaktu se semialogenním plodem, dále vliv na předčasný porod a další těhotenské patologie. Podle posledních údajů se zdá být jejich úloha v imunomodulaci těhotných velmi významná, přestože mnohým mechanismům stále nerozumíme.
Objective: To describe the role of T-regulatory lymphocytes in pathogenesis of preterm delivery. Setting: Department of Obstetrics and Gynecology, General University Hospital and 1st Medical Faculty, Charles University, Prague. Method: T-regulatory lymphocytes modulate the immune system, secure the tolerance to own antigens and prevent autoimmune disease. During pregnancy is maternal immunity in contact with the semi-allogeneic fetus due to the fetomaternal crosstalk. It seems that maternal immunity and T-regulatory lymphocytes have an effect on premature birth and other pregnancy pathologies. According to the latest data, their role in the immunomodulation of pregnant women seems to be very significant, although we still do not understand many mechanisms.
- Publication type
- Meeting Abstract MeSH
Recent discoveries suggest that T-regulatory lymphocytes (Treg) might play an important role in the pathophysiology of preterm labor. The aim of this study was to assess the relationship among the levels of maternal circulating Treg cells, uterine cervical length, and the risk of preterm labor. Sixty women with regular contractions and/or cervical incompetence at 24-32 weeks' gestation were recruited into a prospective study. Each patient underwent transvaginal ultrasound examination of the cervical length, and regulatory T cells were quantified in peripheral blood samples by flow cytometry. Patients with cervical incompetence were prescribed vaginal progesterone until birth. Measurements of Treg levels and cervical length correlated with the timing of labor. The risk of preterm labor happening within 48 h of testing was demonstrated to be almost 35 times higher (OR=35.21, CI 13.3; 214, p<0.001) in the group with simultaneously low Treg values (<0.031 × 10(9)/L) and a shortened uterine cervix (<17.5mm), compared with the situation where both of these values were normal. Similar results were found in predicting preterm delivery before 34 weeks, or between 34 and 37 weeks. A statistically nonsignificant trend toward increased cervical length and increased Treg count was noted in the women on progesterone treatment. We show for the first time that the combined assessment of Treg cell count and cervical length is a much better predictor of preterm delivery than either parameter used on its own. This combined approach may offer clinical application in patients who present with risk factors for preterm labor.
- MeSH
- Cervix Uteri cytology physiology MeSH
- Adult MeSH
- Humans MeSH
- Cervical Length Measurement * MeSH
- Infant, Newborn MeSH
- CD4 Lymphocyte Count * MeSH
- Obstetric Labor, Premature epidemiology immunology physiopathology MeSH
- Progesterone administration & dosage therapeutic use MeSH
- Prospective Studies MeSH
- T-Lymphocytes, Regulatory immunology MeSH
- Risk MeSH
- Pregnancy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Regulatory T cells (Tregs) play a critical role in the maintenance of a pregnancy. While the kinetics of the number of peripheral blood Tregs has been satisfactorily described in mouse models, analysis of these cell populations in human pregnancy is complicated by high variability in the quantity of Tregs and inconsistencies in the markers used for detecting different types of Treg. In the light of this, we set out to investigate the kinetics of various types of Treg, including CD45RA, GARP and PD-1(+) Tregs, in the peripheral blood of pregnant women in the first, second and third trimester, and at the time of delivery. Tregs, defined as a CD4(+)CD25(++)CD127(dim)Foxp3(+) population of leucocytes, were detected using flow cytometry. Natural thymus-derived Tregs and induced Tregs in the peripheral blood were distinguished by the expression or absence of a Helios marker, respectively. Our results showed that during normal pregnancy the sizes of various Treg subpopulations varied across women and also in an individual woman did not remain constant but varied significantly, most notable being the decrease observed at the time of delivery. Helios(-) cells were significantly less frequent in the peripheral blood of healthy pregnant women than Helios(+) cells, and the majority of Tregs were Helios(+)PD-1(+) Tregs.
- MeSH
- Cell Differentiation MeSH
- Forkhead Transcription Factors metabolism MeSH
- Immunophenotyping MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Lymphocyte Count MeSH
- Flow Cytometry MeSH
- T-Lymphocytes, Regulatory immunology MeSH
- T-Lymphocyte Subsets immunology MeSH
- Pregnancy immunology MeSH
- Thymus Gland immunology MeSH
- Transforming Growth Factor beta blood MeSH
- Ikaros Transcription Factor metabolism MeSH
- Healthy Volunteers MeSH
- Check Tag
- Humans MeSH
- Pregnancy immunology MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Allergy is one of the most common diseases with constantly increasing incidence. The identification of prognostic markers pointing to increased risk of allergy development is of importance. Cord blood represents a suitable source of cells for searching for such prognostic markers. In our previous work, we described the increased reactivity of cord blood cells of newborns of allergic mothers in comparison to newborns of healthy mothers, which raised the question of whether or not this was due to the impaired function of regulatory T cells (T(regs)) in high-risk children. Therefore, the proportion and functional properties of T(regs) in cord blood of children of healthy and allergic mothers were estimated by flow cytometry. The proportion of T(regs) [CD4(+)CD25(high)CD127(low) forkhead box protein 3 (FoxP3(+))] in cord blood of children of allergic mothers tends to be higher while, in contrast, the median of fluorescence intensity of FoxP3 was increased significantly in the healthy group. Intracellular presence of regulatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-beta was also higher in T(regs) of children of healthy mothers. Although we detected an increased proportion of T(regs) in cord blood of children of allergic mothers, the functional indicators (intracellular presence of regulatory cytokines IL-10 and TGF-beta, median of fluorescence intensity of FoxP3) of those T(regs) were lower in comparison to the healthy group. We can conclude that impaired function of T(regs) in cord blood of children of allergic mothers could be compensated partially by their increased number. Insufficient function of T(regs) could facilitate allergen sensitization in high-risk individuals after subsequent allergen encounter.
- MeSH
- Hypersensitivity blood immunology MeSH
- CD4 Antigens metabolism MeSH
- Fetal Blood cytology immunology metabolism MeSH
- Forkhead Transcription Factors immunology metabolism MeSH
- Interleukin-10 blood metabolism MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Flow Cytometry MeSH
- Interleukin-2 Receptor alpha Subunit metabolism MeSH
- Interleukin-7 Receptor alpha Subunit metabolism MeSH
- T-Lymphocytes, Regulatory immunology metabolism MeSH
- Case-Control Studies MeSH
- Pregnancy MeSH
- Transforming Growth Factor beta blood metabolism MeSH
- Check Tag
- Humans MeSH
- Infant, Newborn MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
