Immunological Responses to Subcutaneous Allergen Immunotherapy
Richard F. Lockey, Dennis K. Ledford in Allergens and Allergen Immunotherapy, 2014
Identifying the mechanism by which SCIT induces IL-10 producing T cells could be important in the design of new vaccines. Murine models provide some insights. Nevertheless, important differences exist between SCIT administered to patients to modulate mature Th2 responses and animal models where the emphasis is on tolerizing regimens given before sensitization. Tolerizing animals by oral or intranasal exposure to ovalbumin prior to intraperitoneal sensitization induces IL-10 producing regulatory T cells [53,57]. In the intranasal tolerance model, induction of these Tr1-like cells is dependent on pulmonary lymph node DCs expressing IL-10 and the co-stimulatory molecule ICOS ligand. Indeed, adoptive transfer of these DCs or Tr1 cells alone is sufficient to confer tolerance on the recipients [53,58]. Human peripheral blood pDCs stimulated with a TLR 9 agonist express ICOS ligand and induce differentiation of Tr1 cells from naïve T cells in vitro [59]. Furthermore, cross-linking of the high-affinity IgE receptor (FcεRI) on pDCs by allergen also induces IL-10 expression [60]. Although these mechanisms have as yet not been directly implicated during SCIT, they do indicate that DCs could induce T-cell responses following allergen vaccination.
Immunologic responses to various forms of allergen immunotherapy
Richard F. Lockey, Dennis K. Ledford in Allergens and Allergen Immunotherapy, 2020
Identifying the mechanism by which SCIT induces IL-10 producing T cells could be important in the design of new vaccines. Murine models provide some insights. Nevertheless, important differences exist between SCIT administered to patients to modulate mature Th2 responses and animal models where the emphasis is on tolerizing regimes given before sensitization. Tolerizing animals by oral or intranasal exposure to ovalbumin prior to intraperitoneal sensitization induces IL-10 producing regulatory T cells [80,81]. In the intranasal tolerance model, induction of these Tr1-like cells is dependent on pulmonary lymph node dendritic cells expressing IL-10 and the costimulatory molecule ICOS ligand. Indeed, adoptive transfer of these dendritic cells or Tr1 cells alone is sufficient to confer tolerance on the recipients [80,82]. Human peripheral blood pDCs stimulated with a TLR 9 agonist express ICOS ligand and induce differentiation of Tr1 cells from naïve T cells in vitro [83]. Furthermore, cross-linking of the high-affinity IgE receptor (FcεRI) on pDCs by allergen also induces IL-10 expression [84]. Although these mechanisms have not yet been directly implicated during SCIT, they do indicate that dendritic cells could induce T-cell responses following allergen vaccination.
Monoclonal Antibody Mediated Treatment in Acute Myeloid Leukemia
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
The use of murine antibodies in the clinical setting has not been very successful, as they will be recognized by the human immune system as foreign proteins, and generate an human anti-mouse antibody (HAMA) immune reaction (3). This may result in inadequate exposure to the antibody due to diminished stability in the circulation, as well as a severe allergic reaction in the recipient, which interferes with repeated dosing. Murine antibodies also have less capacity to recruit effector cells and complement to destruct cancer cells. They are referred to as “momabs,” such as in ibritumomab, which is directed against the CD20 antigen and used in non-Hodgkin’s lymphoma. The ability to construct so-called “chimeric” or “humanized” antibodies by genetic engineering has markedly improved the possibilities to use monoclonal antibodies in the clinic (4). In chimeric antibodies, the variable region is still from mouse origin, whereas in humanized antibodies this is only the hypervariable region. Chimeric antibodies are approximately 60% to 95% human, whereas humanized antibodies are over 95% human (3). In both instances the murine part is responsible for specificity and antigen recognition. They are referred to as “ximabs” and “zumabs,” respectively, as in rituximab (anti-CD20) and gemtuzumab (anti-CD33) or epratuzumab (anti-CD22). Moreover, fully human antibodies are now available by using transgenic mice that have been engineered to synthesize human antibodies. These antibodies usually allow repeated dosing and do not result in severe allergic reactions.
Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor
Published in mAbs, 2020
Xiaoshan Min, Junming Yie, Jinghong Wang, Ben C. Chung, Ching-Shin Huang, Haoda Xu, Jie Yang, Liying Deng, Joanne Lin, Qing Chen, Christina M. Abbott, Caroline Gundel, Stephen A. Thibault, Tina Meng, Darren L. Bates, David J. Lloyd, Murielle M. Véniant, Zhulun Wang
Antibodies targeting GPCRs provide useful tools to interrogate the complex biology of GPCR. Several antibodies against class B GPCR ECD have been described.28–30 In the case of GIPR, co-crystal structures of an antibody gipg013 with GIPR ECD revealed that the antibody binding site overlaps with the cognate peptide binding site28 and central administration of gipg013 to obese mice leads to lower body weight and food intake.31 Previously we reported that anti-GIPR antibodies co-dosed with glucagon-like peptide-1 receptor (GLP-1R) agonists exhibited enhanced weight loss in non-human primates, providing preclinical validation of a therapeutic potential to treat obesity with anti-GIPR antibodies. In the same study, we also described preliminary proof-of-concept studies of two mouse anti-murine antibodies with distinctive activities in vivo.32 To further understand the underlying molecular mechanism, here we provided in-depth biochemical, cellular, pharmacological and structural characterizations of those two antibodies.
Batf3+ DCs and type I IFN are critical for the efficacy of neoadjuvant cancer immunotherapy
Published in OncoImmunology, 2019
Jing Liu, Elisa A. Rozeman, Jake S. O’Donnell, Stacey Allen, Lorenzo Fanchi, Mark J. Smyth, Christian U. Blank, Michele W.L. Teng
The murine leukemia virus (MuLV) which encodes for the envelope glycoprotein (gp70) is present in many mouse tumor cell lines. While gp70 is normally silent in normal mouse tissue, it can function as a tumor neoantigen in cell lines such as 4T1.2 that express MuLV where tumor-reactive gp70 tetramer-specific CD8+ T cells can be identified5,17,18. The loss of efficacy in Batf3−/- mice correlated with a decrease in the proportion of peripheral blood gp70 tetramer-specific CD8+ T cells in tumor-bearing Batf3−/-, compared to WT mice, following neoadjuvant anti-PD1+anti-CD137 (Figure 1B). Despite this decrease, this data also demonstrated that non-Batf3+ APCs may play a role in the expansion of gp70 tetramer-specific CD8+ T cells in the blood following neoadjuvant immunotherapy, although this was not sufficient to generate any long-term survivors (Figure 1B). We also confirmed that a proportion gp70 tetramer-specific CD8+ T cells in the primary tumor, lung and spleen expressed PD-1 and/or CD137, whether they were treated with neoadjuvant immunotherapy or cIg (Supp. Fig. 1).
cGAS-STING effectively restricts murine norovirus infection but antagonizes the antiviral action of N-terminus of RIG-I in mouse macrophages
Published in Gut Microbes, 2021
Peifa Yu, Zhijiang Miao, Yang Li, Ruchi Bansal, Maikel P. Peppelenbosch, Qiuwei Pan
Noroviruses are positive sense single-stranded RNA viruses belonging to the Caliciviridae family.1 The lack of robust cell culture system for human norovirus (HuNV) impedes development of effective antiviral therapeutics. The closely related murine norovirus (MNV) shares similar structural and genetic features with HuNV and efficiently propagates in vitro and in vivo, representing as a useful model for studying norovirus biology.2 The MNV genome is approximately 7.5 kilo bases in length, consisting of four open reading frames (ORFs). ORF1 encodes a polyprotein that is post-translationally cleaved into six non-structural proteins (NS1/2 to NS7), while ORF2 and ORF3 encode the major and minor structural viral proteins as VP1 and VP2, respectively. ORF4 overlaps with ORF2, and encodes the virulence factor (VF1), which has been reported to antagonize innate immune response.3
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