Oncogenesis and Metastasis
Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple in Basic Urological Sciences, 2021
Immune checkpoint blockade forms the basis of immunotherapy.PD-L1 (programmed cell death protein ligand 1) on tumour cells.PD-1 (programmed cell death protein 1) on T-cells.PD-L1 and PD-1 binding results in T-cell deactivation.PD-L1 and/or PD-1 inhibitor are used in metastatic bladder/renal cancers.CTLA-4 (cytotoxic T-lymphocyte associated protein 4).Expressed by regulatory T-cells.CTLA-4 inhibitors are used in metastatic renal cancer.Inhibitors restore tumour-specific T-cell immunity.
Delivery of Immune Checkpoint Inhibitors Using Nanoparticles
Hala Gali-Muhtasib, Racha Chouaib in Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Regulatory T cells (Tregs) have immunosuppressive functions and inhibit CTLs and other immune cells from performing antitumor effector functions against cancer cells. Elimination or suppression of Tregs can be used to induce anticancer immune responses by removing the inhibition of Tregs on CTLs. In one study, nanoparticles were used to deliver a combination of a Tregs inhibitory molecule (tLyp1 peptide) and a checkpoint inhibitor (CTLA-4 antibody). Administration of the combination NPs decreased the number of intra-tumoral Tregs, increased the number of tumor-specific CTLs, exhibited greater tumor suppression, and prolonged survival of mice injected with melanoma cells as compared to NPs carrying the Tregs inhibitor alone or the checkpoint inhibitor alone [3, 124]. This combination NP can be used in cancers that are resistant to checkpoint inhibition therapy, however, a thorough assessment of in vivo side effects should be warranted, as the risk for immune tolerance related adverse responses will increase.
Clinical Applications of Gene Therapy for Immuno-Deficiencies
Yashwant Pathak in Gene Delivery, 2022
Regulatory T cells (Tregs) prevent autoimmunity as they control immune response to self-antigens. IPEX syndrome develops due to the defects in transcription factor fork head box P3 (FoxP3) that are essential for the normal development and functioning of Tregs. IPEX syndrome clinically presents itself as eczema, enteropathy, and type I diabetes mellitus. Treatment involves prolonged immunosuppression and alloHSCT, but immune-mediated complications can limit its efficacy [83]. The T-cell approach lacks capability for the generation of an adequate amount of Tregs to improve clinical phenotype [84]. HSC-GT is challenging as FoxP3 expression in HSCs prevents proliferation and differentiation of the stem cells. The SIN-LV vector incorporating the endogenous FoxP3 promoter and regulatory elements has shown favourable results that induced lineage-specific expression in progeny of transduced HSCs [84–86].
CNS: Not an immunoprivilaged site anymore but a virtual secondary lymphoid organ
Published in International Reviews of Immunology, 2018
The most distinctive feature of the adaptive immune system is its ability to distinguish self and non-self-antigens and this is more vital for the CNS where over reactive immune responses can lead to CNS damage with life threatening consequences. Evidence gathered in the last few years have suggested that CD25+ T regs are the principal regulators of immune reactions inside the CNS and prevent auto reactive T cells from harming the brain. These cells play a key role in the adaptive immune system by inducing self-tolerance, thereby controlling autoimmune reactions. This subset of T cells, which develops with high avidity to self-antigens, is especially important in controlling autoimmunity [50]. Regulatory T cells are capable of restricting the proliferation and cytokine production from a wide range of immune cells. Besides regulating the function of CD4+T cells, T regs also regulate CD8+T cells, B cells, NKs, natural killer T (NKT) cells, monocytes and macrophages, and DCs. The important functions of T regs inside the CNS in health and disease have not yet been investigated in great detail, hence, it is hard to draw conclusions as to their role in the CNS. Most of the data of CNS T regs has been gathered from diseases that resulted in perturbations of normal homeostatic balance like multiple sclerosis (MS), cerebral vascular diseases (stroke), and glioma [51]. Additionally, T regs have been found to play a key role in experimental autoimmune diseases including EAE.
Association of CD58 Polymorphisms and its Protein Expression with the Development and Prognosis of Autoimmune Thyroid Diseases
Published in Immunological Investigations, 2020
Mayu Yamamoto, Mikio Watanabe, Naoya Inoue, Ayano Watanabe, Haruka Ozaki, Mizuki Ohsaki, Yoh Hidaka, Yoshinori Iwatani
T cells appear to be crucial in the pathogenesis of GD as demonstrated in a mouse model (Saitoh and Nagayama 2006). To activate and differentiate T cells, two signals are required. The first signal is a T cell receptor (TCR) signal to recognize antigen-MHC complexes on antigen-presenting cells (APCs) (Norcross 1984). However, when T cells receive only this signal, they are not activated and go into anergy (Smith et al. 2014). The second signal, a costimulatory signal by the accessory molecules on APCs, is necessary for T cell activation and differentiation (Janeway and Bottomly 1994; Jenkins 1994). Regulatory T cells are promoted to suppress the immune response (Wakkach et al. 2001). Regulatory T cells appear to be crucial in the pathogenesis of GD (Saitoh and Nagayama 2006). We have already shown that intrathyroidal regulatory T cell levels are decreased in AITD patients (Nakano et al. 2007) and that polymorphisms of forkhead box P3 (Foxp3), a master transcription factor of regulatory T cells, is involved in the prognosis of AITDs (Inoue et al. 2010). Therefore, incomplete suppressive activity of regulatory T cells may promote thyroid autoimmunity.
Frequent adaptive immune responses against arginase-1
Published in OncoImmunology, 2018
Evelina Martinenaite, Rasmus Erik Johansson Mortensen, Morten Hansen, Morten Orebo Holmström, Shamaila Munir Ahmad, Nicolai Grønne Dahlager Jørgensen, Özcan Met, Marco Donia, Inge Marie Svane, Mads Hald Andersen
We additionally isolated and expanded specific CD4+ T cells that reacted to peptides derived from the hot-spot region. Our results demonstrated that arginase-1-specific T cells indeed recognized and reacted to DCs and B cells that were electroporated with arginase-1 mRNA. Moreover, targeting arginase-1 towards lysosomal degradation and Class II presentation resulted in increased recognition of electroporated DCs by the arginase-1-specific CD4+ T-cell culture. Although our study focused on arginase-1-specific CD4+ T cells, we also observed CD8+ specific T-cells that were naturally present in some patients. The less frequent CD8+ T cell responses may reflect the fact that long overlapping peptides were used instead of short peptides. Recent evidence supports the view that regulatory T cells have both suppressor and effector capabilities.18 We previously reported that self-reactive pro-inflammatory T cells, termed anti-regulatory T cells (anti-Tregs),19 can specifically target immune-suppressive cells in both the periphery and the tumor microenvironment. This suggests the existence of immune system mechanisms to counteract the immune-suppressive feedback signals mediated by regulatory cells. The presently described arginase-1-specific T cells may indeed be a novel type of anti-Treg.
Related Knowledge Centers
- Cd4
- Downregulation & Upregulation
- Immune Tolerance
- Immunosuppression
- Immune System
- Autoimmune Disease
- T Cell
- Downregulation & Upregulation
- Foxp3
- Il2Ra
- Cell Lineage