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The Immunomodulatory Features of Mesenchymal Stromal Cells Derived from Wharton’s Jelly, Amniotic Membrane, and Chorionic Villi In Vitro and In Vivo Data
Published in Ornella Parolini, Antonietta Silini, Placenta, 2016
Marta Magatti, Mohamed H. Abumaree, Antonietta R. Silini, Rita Anzalone, Salvatore Saieva, Eleonora Russo, Maria Elena Trapani, Giampiero La Rocca, Ornella Parolini
Another costimulatory molecule that belongs to the B7 family is the B7-H3 (CD276) protein. Flow cytometry and immunohistochemical analyses have shown that it is expressed by hWJMSCs (La Rocca et al. 2013b), hAECs (Petroff and Perchellet 2010), and hCVMSCs (Abumaree et al. 2013b). In addition, the molecule has been shown to be expressed not only in naive hWJMSCs but also in their in vitro–differentiated (toward osteogenic, adipogenic, and chondrogenic lineages) counterparts, a characteristic described above also for HLA-G, -E, and -F (La Rocca et al. 2013b). B7-H3 is an important T cell–immunosuppressive molecule that has been reported to consistently downregulate human T cell cytokine production and proliferation (Leitner et al. 2009). Finally, in contrast to PD-L1, PD-L2, and B7-H3, B7-H2 (CD275 or ICOS-L), the ligand for ICOS and provider of positive costimulatory effects promoting T cell activation, differentiation, and effector responses (Coyle et al. 2000; Petroff and Perchellet 2010; Yoshinaga et al. 1999), is not expressed by hAECs (Petroff and Perchellet 2010), hAMSCs (Kronsteiner et al. 2011b), and hCVMSCs (Abumaree et al. 2013b).
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
Although most cases of CVID represent sporadic forms of presentation, pedigrees consistent with autosomal dominant or autosomal recessive inheritance have also been described (Figure 33.2). Association with the human leukocyte antigen (HLA) region has been reported; however, the underlying gene defect has not been identified in most subjects with these disorders. Mutations of the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) have been identified in approximately 10% of patients, most often in heterozygosity. TACI is expressed by B lymphocytes and interacts with the B-cell activating factor (BAFF) and with a proliferation inducing ligand (APRIL). In particular, APRIL and TACI interaction promotes B-cell activation and immunoglobulin class-switch recombination. Disruption of TACI in mice leads to lymphoid proliferation, resembling lymphoid hyperplasia that is often seen in humans with CVID. However, the significance of TACI mutations in CVID pathogenesis remains unclear; with few exceptions, it seems that they may represent susceptibility, rather than disease-causing mutations. A similar significance of CVID-predisposing factors has also been attributed to mutations of BAFF receptor (BAFF-R) and CD20, reported in a few patients with CVID. In contrast, a clear causal role has been demonstrated for mutations of ICOS, CD19, and CD81. ICOS is a costimulatory molecule, expressed by T cells, that interacts with ICOS-ligand (ICOS-L) expressed by B lymphocytes. CD19 and CD81 form a cell-surface protein complex that participates in BCR-mediated signaling. Patients with CVID are highly prone to a variety of gastrointestinal manifestations (Table 33.2), including infections, autoimmunity, inflammation, and tumors. In addition, abnormalities of liver function have been reported.
CTLA4-Ig (abatacept): a promising investigational drug for use in type 1 diabetes
Published in Expert Opinion on Investigational Drugs, 2020
Ousama Rachid, Aisha Osman, Reza Abdi, Yousef Haik
In a study exploring the possible mechanism of abatacept resistance, abatacept-treated subjects were grouped into respondents (Rs) and non-respondents (NRs) based on the rate of the progression of type 1 diabetes, measured by C-peptide decline [81]. It was concluded that differential expression of B-cell genes, either individually or modularly, can be used to predict disease progression in both R and NR individuals of the abatacept-treated group after 84 days. These differences seemed to be transient and subsided after 2 years and were not evident when the abatacept-treated group was compared to placebo. Furthermore, the transient B-cell gene expression differences were linked to differential expression of T cell costimulatory ligands including ICOSLG, CD40, and CD58 between R and NR groups. This suggests a reprogramming mechanism of the CD28/CD80/CD86 T cell co-stimulation in response to abatacept therapy, leading to the observed resistance in the poor response group. This study together with others suggest the association of B cells, T cells, neutrophils, and other cell types with abatacept response and resistance in R and NR groups, respectively [77,80,81].
Lack of MHC class II molecules favors CD8+ T-cell infiltration into tumors associated with an increased control of tumor growth
Published in OncoImmunology, 2018
Nada Chaoul, Alexandre Tang, Belinda Desrues, Marine Oberkampf, Catherine Fayolle, Daniel Ladant, Alexander Sainz-Perez, Claude Leclerc
CD39 expression was also significantly increased on tumor Tregs, but since CD73 is significantly reduced, these results suggest that tumor Tregs do not exert their immunosuppressive activity through the up-regulation of intracellular AMP via the CD39-CD73 pathway. Recent studies have shown that highly suppressive Tregs that accumulate in tumors are characterized by increased expression of ICOS.24,25 Since we also observed increased expression of ICOS on tumor and dLN Tregs, this finding suggests that inhibition of the ICOS-ICOS-L pathway could be a promising strategy for enhancing the anti-tumor immune response. Similar results were obtained for the CD103 molecule, which was significantly increased on tumor and dLN Tregs. CD103 was shown to be a hallmark of tumor-infiltrating Tregs.23 However, this integrin, which is required for T-cell homing to the intestinal mucosa, is also expressed by T lymphocytes in epithelial tissues59 and by tissue-resident innate lymphoid cells and innate-like T cells.60 Importantly, resident memory cells (Trm), defined by the expression of CD103 and CD69, were recently shown to play a key role in the efficacy of cancer vaccine to inhibit tumor growth.61 In agreement with these findings, the expression of CD103 was also significantly increased on tumor-infiltrating Teffs.
Role of Inducible Co-Stimulator (ICOS) in cancer immunotherapy
Published in Expert Opinion on Biological Therapy, 2020
Florent Amatore, Laurent Gorvel, Daniel Olive
The expression of ICOSL was demonstrated to be boosted by inflammatory cytokines including TNF-α [15]. Therefore, the upregulation of ICOSL on endothelial cells provides the recruitment of effector T-cells into tissues under inflammatory conditions [16]. For example, during human cardiac allograft rejection, endothelial ICOSL expression is increased leading to EC-mediated CD8+ T cell co-stimulation [63] and CD8+ memory T-cell activation [64]. Interestingly, ICOS can deliver a reverse signal through ICOSL. First, the engagement of ICOSL produces a stimulatory synergistic effect, as shown for NOD2 (nucleotide-binding oligomerization domain 2)-driven cytokine secretion [65]. Moreover, signaling through ICOSL has a direct effect on DCs, promoting the secretion of IL-6 [66] via the phosphorylation of p38-MAPK. Furthermore, the Fc fragment of ICOS can stimulate monocyte-derived dendritic cells (MDDCs) through ICOSL during lipopolysaccharide-driven maturation and exacerbates IL-23, IL-10 secretion, which promoted Th17 polarization in mixed lymphocyte culture [67]. The expression of ICOS or ICOS-L by tumor cells is logically more the prerogative for hematologic diseases. However, the expression of ICOS-L has been found on glioma cells (but not in adjacent normal central nervous system tissues) [68], colorectal cancer [47] and melanoma [52]. Indeed, ICOS-L is expressed by malignant melanoma cells, which promotes the expansion of ICOS+ IL-10-secreting Tregs via ICOS/ICOSL pathway [52]. The expression of ICOS-L by melanoma cells and pDCs have been described to be type 1 IFN dependent [51,52]. Thereby, ICOS-L expression by melanoma tumor cells could favor immune escape by driving Treg expansion and survival.