Nonspecific cytotoxic cells of teleosts are armed with multiple granzymes and other components of the granule exocytosis pathway

Praveen, Kesavannair; Leary, John H.; Evans, Donald L.; Jaso-Friedmann, Liliana

doi:10.1016/j.molimm.2005.07.027

Cited by 37 publications

(31 citation statements)

References 37 publications

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“…Given the polar variability in the expression of these 16 transcripts, they serve as distinguishing marks for the 2 immune states defined by breakthrough acute vs hyperacute disease ( Figure 5C; supplemental Table 5). These transcripts defined a dichotomy between hyperacute and breakthrough acute GVHD that included a pivot around (1) cytotoxicity (SLAMF7, 22 CMA1, 23,24 CST7, 25 each underrepresented in breakthrough acute GVHD), (2) apoptosis (FASL 26,27 and IGF2R, 28,29 proapoptotic genes underrepresented in breakthrough acute GVHD and KIAA1324 30 and IRS1, 31,32 antiapoptotic genes overrepresented in breakthrough acute GVHD), and (3) Th/Tc17 programming (ADAM12 33 and RORC, 34 overrepresented in breakthrough acute disease).…”

Section: -21mentioning

confidence: 99%

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

Furlan

Watkins

Tkachev

et al. 2016

Blood

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• The transcriptional networks controlling breakthrough acute GVHD can be mapped, and correlate closely with clinical disease.• Breakthrough acute GVHD is transcriptionally controlled by T-cell persistence, inflammation, and Th/Tc17 skewing.One of the central challenges of transplantation is the development of alloreactivity despite the use of multiagent immunoprophylaxis. Effective control of this immune suppression-resistant T-cell activation represents one of the key unmet needs in the fields of both solid-organ and hematopoietic stem cell transplant (HCT). To address this unmet need, we have used a highly translational nonhuman primate (NHP) model to interrogate the transcriptional signature of T cells during breakthrough acute graftversus-host disease (GVHD) that occurs in the setting of clinically relevant immune suppression and compared this to the hyperacute GVHD, which develops in unprophylaxed or suboptimally prophylaxed transplant recipients. Our results demonstrate the complex character of the alloreactivity that develops during ongoing immunoprophylaxis and identify 3 key transcriptional hallmarks of breakthrough acute GVHD that are not observed in hyperacute GVHD: (1) T-cell persistence rather than proliferation, (2) evidence for highly inflammatory transcriptional programming, and (3) skewing toward a T helper (Th)/T cytotoxic (Tc)17 transcriptional program. Importantly, the gene coexpression profiles from human HCT recipients who developed GVHD while on immunosuppressive prophylactic agents recapitulated the patterns observed in NHP, and demonstrated an evolution toward a more inflammatory signature as time posttransplant progressed. These results strongly implicate the evolution of both inflammatory and interleukin 17-based immune pathogenesis in GVHD, and provide the first map of this evolving process in primates in the setting of clinically relevant immunomodulation. This map represents a novel transcriptomic resource for further systems-based efforts to study the breakthrough alloresponse that occurs posttransplant despite immunoprophylaxis and to develop evidence-based strategies for effective treatment of this disease. (Blood. 2016;128(21):2568-2579

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Section: -21mentioning

confidence: 99%

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

Furlan

Watkins

Tkachev

et al. 2016

Blood

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“…Knowledge about fish perforin genes is scarce, and these genes have only been characterized in 4 species [8,9,10,11]. Contrary to what occurs in higher vertebrates, fish species have more than 1 perforin gene in their genomes.…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory Caspase A Activation and an Antiviral State Are Induced by a Zebrafish Perforin after Possible Cellular and Functional Diversification from a Myeloid Ancestor

et al. 2015

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In mammals, perforins play a central role in the granule-dependent cell death induced by natural killer T cells and cytotoxic T lymphocytes, and participate both in the defense against virus-infected and neoplastic cells and in the recognition of nonself molecules by the immune system. Little is known about fish perforin genes. We examined the zebrafish with the aim of increasing our knowledge about the role of perforins. We characterized 6 perforin genes in the zebrafish genome, and we studied them at the evolutionary level in combination with expression patterns in several tissues and cell populations, during both larval development and in the course of a viral infection. Our results suggest the specialization of different cell types in the production of perforins. Moreover, functional diversification during the evolution of these molecules could be inferred from this study. In particular, one of the genes, prf19b, which is mainly produced by myeloid cells, seemed to be involved in antiviral defense, conferring protection after an in vivo infection.

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“…Innate immunity, being the fi rst defensive line against microorganisms, is fundamental to avoid infectious diseases (Plouffe et al 2005). Among the cellular components of innate immunity we can include natural cytotoxic cells (NCCs), functionally homologous to natural killer cells (NK) of mammals (Evans & Jaso-Friedmann 1992;Praveen et al 2006). One of the main functions of NCCs is to eliminate, without the requirement of a previous contact or recognition, intracellularly infected or transformed cells by lysing them or inducing their apoptosis (Praveen et al 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Among the cellular components of innate immunity we can include natural cytotoxic cells (NCCs), functionally homologous to natural killer cells (NK) of mammals (Evans & Jaso-Friedmann 1992;Praveen et al 2006). One of the main functions of NCCs is to eliminate, without the requirement of a previous contact or recognition, intracellularly infected or transformed cells by lysing them or inducing their apoptosis (Praveen et al 2006). Other important effectors of the innate response in fi sh are macrophages (Secombes 1996).…”

Section: Introductionmentioning

confidence: 99%

In vitro effect of Levamisole on Rainbow Trout (Oncorhynchus mykiss) peripheral blood mononuclear cells

2015

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The in vitro effect of levamisole (1, 10 and 100 μg/ml) on cells of the innate immune response of rainbow trout (Oncorhynchus mykiss) was studied, particularly the activity of natural cytotoxic cells and macrophages present in peripheral blood. Levamisole effect on natural cytotoxic cells was evaluated by their capacity to lyse HL-60 tumor cells while activity of macrophages was evaluated measuring production of reactive oxygen species and nitric oxide. Results indicate that natural cytotoxic cells activity was signifi cantly increased by 1 μg/ml levamisole and that higher doses had no effect. On the other hand, reactive oxygen species and nitric oxide production by macrophages was not increased by any of the levamisole doses used and that the higher dose (100 μg/ml) induced a signifi cant decrease of nitric oxide levels, which might be deleterious for the defensive response of these fi sh. KEYWORDS:Innate immunity; reactive oxygen species; ROS; nitric oxide. RESUMENSe estudió el efecto in vitro del levamisol (1, 10 y 100 μg/ml) sobre células de la respuesta inmune innata de trucha arcoíris (Oncorhynchus mykiss), particularmente la actividad de las células citotóxicas naturales y de los macrófagos presentes en sangre periférica. El efecto del levamisol sobre las células citotóxicas naturales fue evaluado mediante su capacidad para lisar células tumorales HL-60, mientras que la actividad de los macrófagos fue evaluado mediante la producción de especies reactivas del oxígeno y de óxido nítrico. Los resultados indican que la actividad de las células citotóxicas naturales fue incrementada signifi cativamente por 1 μg/ml levamisol mientras que dosis mayores no produjeron este efecto. Por otro lado, la producción de especies reactivas del oxígeno y de óxido nítrico por los macrófagos no fue incrementada por ninguna de las dosis usadas, sin embargo dosis de 100 μg/ml indujeron una disminución signifi cativa en los niveles de óxido nítrico, lo cual podría ser deletéreo para la respuesta defensiva de estos peces. PALABRAS CLAVES:Inmunidad innata; especies reactivas del oxígeno; ROS; óxido nítrico.

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Nonspecific cytotoxic cells of teleosts are armed with multiple granzymes and other components of the granule exocytosis pathway

Cited by 37 publications

References 37 publications

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

Proinflammatory Caspase A Activation and an Antiviral State Are Induced by a Zebrafish Perforin after Possible Cellular and Functional Diversification from a Myeloid Ancestor

In vitro effect of Levamisole on Rainbow Trout (Oncorhynchus mykiss) peripheral blood mononuclear cells

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