Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1-/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1-/- mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.
- MeSH
- Alagillův syndrom patologie genetika MeSH
- buněčná diferenciace * MeSH
- hepatocyty * metabolismus patologie MeSH
- jaterní cirhóza * patologie genetika MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- protein jagged-1 * metabolismus genetika MeSH
- regulační T-lymfocyty imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.
- MeSH
- cytokiny metabolismus MeSH
- interleukin-2 * imunologie MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory imunologie terapie farmakoterapie MeSH
- proteinové inženýrství metody MeSH
- regulační T-lymfocyty imunologie účinky léků MeSH
- rekombinantní fúzní proteiny * farmakologie imunologie aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Chlamydia psittaci pneumonia (CPP) is a lung disease caused by the infection with the Chla-mydia psittaci bacterium, which can lead to severe acute respiratory distress syndrome and systemic symptoms. This study explored the specific mechanisms underlying the impact of reactive oxygen species (ROS) on the Th17/Treg balance in CPP. The levels of ROS and the differentiation ratio of Th17/Treg in the peripheral blood of healthy individuals and CPP patients were measured using ELISA and flow cytometry, respectively. The association between the ROS levels and Th17/Treg was assessed using Pearson correlation analysis. The ROS levels and the Th17/Treg ratio were measured in CD4+ T cells following H2O2 treatment and NLRP3 inhibition. The effects of H2O2 treatment and NLRP3 inhibition on the NLRP3/IL-1β/caspase-1 pathway were observed using immunoblotting. Compared to the healthy group, the CPP group exhibited increased levels of ROS in the peripheral blood, an elevated ratio of Th17 differentiation, and a decreased ratio of Treg differentiation. ROS levels were positively correlated with the Th17 cell proportion but negatively correlated with the Treg cell proportion. The ROS levels and NLRP3/IL-1β/caspase-1 expression were up-regulated in CD4+ T cells after H2O2 treatment. Furthermore, there was an increase in Th17 differentiation and a decrease in Treg differentiation. Conversely, the NLRP3/IL-1β/caspase-1 pathway inhibition reversed the effects of H2O2 treatment, with no significant change in the ROS levels. ROS regulates the Th17/Treg balance in CPP, possibly through the NLRP3/IL-1β/caspase-1 pathway. This study provides a new perspective on the development of immunotherapy for CPP.
- MeSH
- buněčná diferenciace * účinky léků MeSH
- buňky Th17 * imunologie metabolismus MeSH
- Chlamydophila psittaci * MeSH
- dospělí MeSH
- interleukin-1beta * metabolismus MeSH
- kaspasa 1 * metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- peroxid vodíku metabolismus MeSH
- protein NLRP3 * metabolismus MeSH
- psitakóza MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- regulační T-lymfocyty * imunologie MeSH
- signální transdukce MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Suppressive function of regulatory T cells (Treg) is dependent on signaling of their antigen receptors triggered by cognate self, dietary, or microbial peptides presented on MHC II. However, it remains largely unknown whether distinct or shared repertoires of Treg TCRs are mobilized in response to different challenges in the same tissue or the same challenge in different tissues. Here we use a fixed TCRβ chain FoxP3-GFP mouse model to analyze conventional (eCD4) and regulatory (eTreg) effector TCRα repertoires in response to six distinct antigenic challenges to the lung and skin. This model shows highly 'digital' repertoire behavior with easy-to-track challenge-specific TCRα CDR3 clusters. For both eCD4 and eTreg subsets, we observe challenge-specific clonal expansions yielding homologous TCRα clusters within and across animals and exposure sites, which are also reflected in the draining lymph nodes but not systemically. Some CDR3 clusters are shared across cancer challenges, suggesting a response to common tumor-associated antigens. For most challenges, eCD4 and eTreg clonal response does not overlap. Such overlap is exclusively observed at the sites of certain tumor challenges, and not systematically, suggesting transient and local tumor-induced eCD4=>eTreg plasticity. This transition includes a dominant tumor-responding eCD4 CDR3 motif, as well as characteristic iNKT TCRα CDR3. In addition, we examine the homeostatic tissue residency of clonal eTreg populations by excluding the site of challenge from our analysis. We demonstrate that distinct CDR3 motifs are characteristic of eTreg cells residing in particular lymphatic tissues, regardless of the challenge. This observation reveals the tissue-resident, antigen-specific clonal Treg populations.
- MeSH
- buněčné klony MeSH
- CD4-pozitivní T-lymfocyty * MeSH
- myši MeSH
- peptidy MeSH
- receptory antigenů T-buněk genetika MeSH
- regulační T-lymfocyty * MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: In chronic lymphocytic leukemia (CLL), changes in the peripheral blood lymphocyte subsets play an important role in disease progression and infectious complications. The impact of chemoimmunotherapy (CIT) on these changes has not been extensively studied METHODS: We used multi-color flow cytometry, to prospectively measure absolute and relative numbers of CD4+ and CD8+ T-cells and their subsets in 45 patients with indolent untreated CLL, 86 patients indicated for first-line treatment, and 34 healthy controls. In 55 patients, we analyzed the impact of CIT RESULTS: CLL patients had a significant increase in most cell populations in comparison to controls. Progression of CLL was characterized by significantly elevated counts with the exception of a lower percentage of naïve T-cells. After treatment, the percentage of naïve T-cells further decreased at the expense of effector memory T-cells (TEM). In patients with indolent CLL, higher percentages of naïve CD4+ (p = 0.0026) and naïve CD8+ (p = 0.023) T-cells were associated with a longer time to first treatment (TTFT). The elevation of CD4+ central memory T-cells (TCM) (p = 0.27) and TEM (p = 0.003) counts and a higher percentage of CD4+ TEM (p = 0.0047), were linked with shorter TTFT. In treated patients, increased regulatory T-cells count was associated with shorter time to next treatment (TTNT) (p = 0.042), while higher CD4+ TCM count with shorter TTNT (p = 0.035) and shorter overall survival (p = 0.041). CONCLUSION: Our results indicate that naïve cell depletion and CD4+ TCM and TEM increases are detrimental to CLL patients' prognosis.
As the body's integumentary system, the skin is vulnerable to injuries. The subsequent wound healing processes aim to restore dermal and epidermal integrity and functionality. To this end, multiple tissue-resident cells and recruited immune cells cooperate to efficiently repair the injured tissue. Such temporally- and spatially-coordinated interplay necessitates tight regulation to prevent collateral damage such as overshooting immune responses and excessive inflammation. In this context, regulatory T cells (Tregs) hold a key role in balancing immune homeostasis and mediating cutaneous wound healing. A comprehensive understanding of Tregs' multifaceted field of activity may help decipher wound pathologies and, ultimately, establish new treatment modalities. Herein, we review the role of Tregs in orchestrating the regeneration of skin adnexa and catalyzing healthy wound repair. Further, we discuss how Tregs operate during fibrosis, keloidosis, and scarring.
- MeSH
- hojení ran * fyziologie MeSH
- kůže MeSH
- lidé MeSH
- regulační T-lymfocyty * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Transplant rejection remains a challenge especially in the field of vascularized composite allotransplantation (VCA). To blunt the alloreactive immune response' stable levels of maintenance immunosupression are required. However' the need for lifelong immunosuppression poses the risk of severe side effects, such as increased risk of infection, metabolic complications, and malignancies. To balance therapeutic efficacy and medication side effects, immunotolerance promoting immune cells (especially regulatory T cells [Treg]) have become of great scientific interest. This approach leverages immune system mechanisms that usually ensure immunotolerance toward self-antigens and prevent autoimmunopathies. Treg can be bioengineered to express a chimeric antigen receptor or a T-cell receptor. Such bioengineered Treg can target specific antigens and thereby reduce unwanted off-target effects. Treg have demonstrated beneficial clinical effects in solid organ transplantation and promising in vivo data in VCAs. In this review, we summarize the functional, phenotypic, and immunometabolic characteristics of Treg and outline recent advancements and current developments regarding Treg in the field of VCA and solid organ transplantation.
Transplant rejection remains a challenge especially in the field of vascularized composite allotransplantation (VCA). To blunt the alloreactive immune response' stable levels of maintenance immunosupression are required. However' the need for lifelong immunosuppression poses the risk of severe side effects, such as increased risk of infection, metabolic complications, and malignancies. To balance therapeutic efficacy and medication side effects, immunotolerance promoting immune cells (especially regulatory T cells [Treg]) have become of great scientific interest. This approach leverages immune system mechanisms that usually ensure immunotolerance toward self-antigens and prevent autoimmunopathies. Treg can be bioengineered to express a chimeric antigen receptor or a T-cell receptor. Such bioengineered Treg can target specific antigens and thereby reduce unwanted off-target effects. Treg have demonstrated beneficial clinical effects in solid organ transplantation and promising in vivo data in VCAs. In this review, we summarize the functional, phenotypic, and immunometabolic characteristics of Treg and outline recent advancements and current developments regarding Treg in the field of VCA and solid organ transplantation.
The therapeutic potential of interleukin (IL)-2 in cancer treatment has been known for decades, yet its widespread adoption in clinical practice remains limited. Recently, chimeric proteins of an anti-PD-1 antibody and suboptimal IL-2 variants were shown to stimulate potent antitumor and antiviral immunity by inducing unique effector CD8+ T cells in mice. A similar subset of cytotoxic T cells is induced by depletion of regulatory T cells (Tregs), suggesting IL-2 sequestration as a major mechanism through which regulatory T cells suppress activated CD8+ T cells. Here, we present our view of how IL-2-based biologicals can boost the antitumor response at a cellular level, and propose that the role of Tregs following such treatments may have been previously overestimated.
- MeSH
- CD8-pozitivní T-lymfocyty * MeSH
- cytotoxické T-lymfocyty MeSH
- fenotyp MeSH
- imunoterapie MeSH
- interleukin-2 * terapeutické užití metabolismus MeSH
- myši MeSH
- regulační T-lymfocyty MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Imunoterapie jako samostatná léčebná modalita nebo v kombinaci s chemoterapií se stala novým zlatým standardem léčby nemocných s recidivujícími či metastazujícími nádory hlavy a krku s vyčerpanými možnostmi lokoregionální terapie. V naší kazuistice prezentujeme pacienta s recidivou nádoru hlasivky po kurativní radioterapii a následně první linii paliativní léčby cisplatinou s 5-fluorouracilem s rychlou progresí onemocnění, druhou linií imunoterapie nivolumabem, po které následovala opět progrese, a teprve po třetí linii s docetaxelem došlo k dlouhodobé kompletní remisi onemocnění. Tuto skutečnost si vysvětlujeme buď opožděnou aktivací imunitního systému, nebo imunomodulačním účinkem docetaxelu, jelikož dlouhodobá kompletní remise po třetí linii paliativní léčby docetaxelem se nedá úplně očekávat.
Immunotherapy as monotherapy or in combination with chemotherapy represents the new gold standard for the treatment of the relapsed or metastatic head and neck cancer where local therapy is not possible. In our case report we present the patient with laryngeal cancer relapse after radical radiotherapy and first line palliative chemotherapy cisplatin and 5-fluorouracil with rapid disease progression followed by second line palliative treatment with immunotherapy nivolumab, again with progression and finally followed by third line palliative treatment with docetaxel with long term complete remission. This excellent result can be explained by delayed activation of the immune system or immunomudulatory effect of the docetaxel, since long term remission cannot be expected solely after third line docetaxel palliative treatment.
- MeSH
- adjuvantní chemoterapie MeSH
- analýza přežití MeSH
- cetuximab terapeutické užití MeSH
- cisplatina terapeutické užití MeSH
- docetaxel terapeutické užití MeSH
- fluorouracil terapeutické užití MeSH
- hlasové řasy patologie MeSH
- imunoterapie MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- metastázy nádorů MeSH
- nádory hrtanu * farmakoterapie MeSH
- nivolumab terapeutické užití MeSH
- PET/CT MeSH
- progrese nemoci MeSH
- protinádorové látky imunologicky aktivní terapeutické užití MeSH
- regulační T-lymfocyty účinky léků MeSH
- senioři MeSH
- spinocelulární karcinom MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
