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Soluble Mediators of Cellular Cooperation: The Cytokines
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Recently, the locus harboring the genetic defect in X-linked severe combined immunodeficiency disease (XSCID, see Chapter 2) was found to be identical to the IL-2Ry gene. The genes from three different patients with XSCID have been analyzed, all have been found to contain different mutations of the IL-2Ry gene. Subsequently, the same γ chain has been shown also to be a component of the receptors for interleukins 4,7,9, and 15, and is now referred to as yc, the “common” γ chain. Thus, mutation of this single protein disrupts at least five cytokine pathways.
Gene Transfer into Human Hematopoietic Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Serguei Kisselev, Tatiana Seregina, Richard K. Burt, Charles J. Link
Cavazzano-Calvo and colleagues describing 5 successful attempts to correct X-linked severe combined immunodeficiency (SCID-X1) by transplantation of autologous CD34+ cells transduced ex vivo with the common gamma chain (yc) gene.109,110 The restoration of normal lymphopoiesis in patients occurred secondary to an apparent selective advantage acquired by T-cell progenitors derived from gene modified HSC expressing the wild type version of yc gene. Another key result of this clinical trial was long-term engraftment (at least 30 months) of genetically modified BM after transplantation. This study demonstrated that retroviral mediated gene transfer into whole CD34+ populations allows transduction of multipotential HSC with clinically significant expression of the therapeutic gene. The activation protocol used in the trial (SCF, FLT3-L, IL-3, and megakaryocyte growth factor) appears to allow transduction of HSC without differentiation. It should be noted that this trial was conducted in children, and it is possible that part of the success of gene transfer into HSC is dependent on the young age of the donor’s HSC.
Clinical Potential of Gene Expression Imaging
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Immunogenicity of the reporter is not desirable in most circumstances since it may result in an immune response and potentially kill transduced cells, prevent repeated administration of the therapy, and worse, possibly cause an anaphylactic reaction. Nonimmunogenic reporters are desirable for many applications, but may not be needed if a goal of the gene therapy is to induce an immune response, as may be the case for some cancer therapies. It has been noted that donor lymphocytes transduced to express HSV-TK elicit a strong immune response to this transgene and the response increases with repeated exposure (24). Berger et al. (25) also found that the T-cell response to HSV-TK recognized multiple epitopes, suggesting modifications of immunogenic sequences in the transgene are unlikely to be effective in humans, where the diversity of human leukocyte antigen (HLA) alleles will allow the recognition of multiple immunogenic epitopes and intimates that introduction of HSV-TK may be used to boost immunity to transduced cells or contemporaneously introduced therapeutic genes. Predictably, Traversari et al. suggest that the immune response is dependent on the degree of immunocompetence, with greater response occuring with greater immunocompetence, and that immunogenic reporter genes may be useful in appropriately immunocompromised patients (26). Such findings suggest that using immunogenic reporters will limit not only cell-trafficking studies, particularly of autologous stem cells for tissue repair and regeneration, but may also lead to the death of transduced cells when such a reporter is used with another gene. This is a problem for nonlethal gene therapies such as for diabetes or X-linked severe combined immunodeficiency, where the goal is to maintain expression of the gene of interest. It may also be a problem for interpretation of lethal gene therapies, because one has to separate the effect of the reporter from that of the therapeutic gene. Inflammation can also interfere with assessment of other modalities for analyzing efficacy, including CT, MR, and more so 18F-FDG PET. In addition, immunogenicity may limit repetitive dosing, which will be desirable in many gene therapy situations since gene expression very commonly wanes with time, particularly with popular vectors such as adenovirus or lipid-based formulations. Use of human genes as reporters is desirable. Traversari et al. found that cells expressing foreign genes are targets of an immune response, whereas endogenous proteins commonly are not, even if ectopically expressed in a context otherwise extremely immunogenic (26). The D2R reporter system described is based on the rat sequence, thus, has potential for immunogenicity. A new system based on human mitochondrial TK expression in the cytosol has been recently described. A truncated form of the TK functioned as a superior reporter compared with the nontruncated form (27), but the truncated form phosphorylated the substrate FIAU approximately five times less than did HSV1-TK; yet, it could be imaged in vivo (28). Since it is a human protein, it may be less immunogenic; however, this needs further study since inappropriate subcellular localization of proteins can lead to immunogenicity. Fortunately, both the SSTR2 and the NIS are human proteins.
Ex vivo gene therapy for lysosomal storage disorders: future perspectives
Published in Expert Opinion on Biological Therapy, 2023
Edina Poletto, Andrew Oliveira Silva, Ricardo Weinlich, Priscila Keiko Matsumoto Martin, Davi Coe Torres, Roberto Giugliani, Guilherme Baldo
However, to produce optimal results, some important issues still need to be addressed. Some of these issues are related to the availability of patients. For example, due to their low frequency and unspecific symptoms and signs, often LSD patients are diagnosed later in life, when a gene therapy procedure is less likely to produce major benefits. To solve this, early-diagnosis strategies such as newborn screening need to be considered. Other issues are related to the gene therapy procedure per se. In particular, one important point that still needs to be addressed more carefully is genotoxicity and cellular transformation, which has been shown in past gene therapy trials for other conditions, such as X-linked severe combined immunodeficiency (SCID). Even with new techniques that allow gene insertion at a more precise spot, such as genome editing systems, off target effects are still a possibility, and detecting these events when at a very low frequency can be challenging.
Immunotherapy with NK cells: recent developments in gene modification open up new avenues
Published in OncoImmunology, 2020
Lisa Marie Reindl, Nawid Albinger, Tobias Bexte, Stephan Müller, Jessica Hartmann, Evelyn Ullrich
Different systems, which can be classified as viral and nonviral technologies, can be used for the genetic modification of NK cells and NK cell lines. Many viral vector systems, including alpharetroviral (α-RV), gammaretroviral (γ-RV) and lentiviral (LV) systems have been developed, with retroviral vectors being the most commonly used (for review see Matosevic et al.).73 Transduction efficiencies differ between published studies and depend on the NK cell source, the viral vector system and the transduction enhancer used.73 For instance, γ-RV vector systems have achieved high transduction efficiencies in expanded PB- and UCB-derived NK cells.74–76 Interestingly, most protocols used gene-modified K562 feeder cells expressing membrane-bound cytokines (mbIL-21 or IL-15) and 4–1BB to enhance NK cell expansion and potentially improve the transduction efficiency. It is still unknown whether high transduction rates solely depend on the γ-RV vectors or whether other conditions play a significant role as well. Nevertheless, the use of γ-RV vectors is associated with the risk of insertional mutagenesis and oncogenesis. In a study of X-linked severe combined immunodeficiency (SCID), nine out of ten patients were cured using γ-RV-mediated gene therapy, but four of them developed T cell leukemia, indicating the need for viral vector systems with a safer integration pattern and a decreased risk of insertion mutation (i.e., LV and α-RV vectors or a nonviral approach).77,78
JAK3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys
Published in Islets, 2019
Jong-Min Kim, Jun-Seop Shin, Byoung-Hoon Min, Seong-Jun Kang, Il-Hee Yoon, Hyunwoo Chung, Jiyeon Kim, Eung-Soo Hwang, Jongwon Ha, Chung-Gyu Park
Recently, significant attention has been paid to develop Janus kinase 3 (JAK3) inhibitor as a novel immunosuppressive drug in organ transplantation, because this class of inhibitor can be theoretically appealing for several reasons.9 First, the mutation in the gene encoding JAK3, a cytoplasmic tyrosine kinase resulted in a phenotype similar to X-linked severe-combined immunodeficiency disease (X-SCID), which is characterized by immune deficiency such as T−B+NK− cell phenotype. Second, JAK3 has a more restricted expression pattern than other JAKs such that it is expressed at high levels in immune cells. Third, JAK3 is tightly associated with the cytokine receptor subunit, common γ chain, which is important for signal transduction of many cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Thus, JAK3 inhibitor would inhibit the function of T cells, B cells, NK cells, memory T cells through IL-2, IL-4, IL7, IL-15 signaling pathway, respectively. Consistent with this notion, Busque et al. recently reported that long-term tofacitinib was effective in preventing renal allograft acute rejection and preserving renal function in open-label, long-term extension (LTE) study.10 All these features led us to hypothesize that JAK3 inhibitor may replace tacrolimus in immunosuppressive regimen in allogeneic islet transplantation setting. To test this hypothesis, clinically available JAK3 inhibitor, tofacitinib, was used in replacement with tacrolimus in CIT07 immunosuppressive regimen in cynomolgus monkey allogeneic islet transplantation model.