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Article: Transplantation tolerance: lessons from experimental rodent models.

Kingsley, Cherry I / Nadig, Satish N / Wood, Kathryn J

Transplant international : official journal of the European Society for Organ Transplantation

2007 Volume 20, Issue 10, Page(s) 828–841

Abstract: Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, ... ...

Abstract	Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, rodent models have become an invaluable tool for elucidating the mechanisms of tolerance to alloantigens. Importantly, rodent models can be adapted to ensure that they reflect more accurately the immune status of human transplant recipients. More recently, the development of genetically modified mice has enabled specific insights into the cellular and molecular mechanisms that play a key role in both the induction and maintenance of tolerance to be obtained and more complex questions to be addressed. This review highlights strategies designed to induce alloantigen specific immunological unresponsiveness leading to transplantation tolerance that have been developed through the use of experimental models.
MeSH term(s)	Animals ; Disease Models, Animal ; Graft Survival/immunology ; Immune Tolerance ; Immunity, Cellular/immunology ; Organ Transplantation ; Rodentia ; T-Lymphocytes/immunology
Language	English
Publishing date	2007-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639435-8
ISSN	1432-2277 ; 0934-0874
ISSN (online)	1432-2277
ISSN	0934-0874
DOI	10.1111/j.1432-2277.2007.00533.x
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Article: Pretransplant blood transfusion without additional immunotherapy generates CD25+CD4+ regulatory T cells: a potential explanation for the blood-transfusion effect.

Bushell, Andrew / Karim, Mahzuz / Kingsley, Cherry I / Wood, Kathryn J

Transplantation

2003 Volume 76, Issue 3, Page(s) 449–455

Abstract: Background: Preoperative blood transfusion has had a significant historic impact on graft outcome in clinical kidney transplantation, and the effect has been widely replicated in many experimental transplant models. Although the mechanisms underlying ... ...

Abstract	Background: Preoperative blood transfusion has had a significant historic impact on graft outcome in clinical kidney transplantation, and the effect has been widely replicated in many experimental transplant models. Although the mechanisms underlying the blood-transfusion effect are poorly understood, one possibility is that preexposure to alloantigen results in the induction of regulatory cells with the capacity to control the effector arm of the immune response. Methods: Recent studies in autoimmune models have shown that T cells with regulatory function can be isolated from unmanipulated animals on the basis of CD25 expression, and we have recently shown that pretreatment of recipient mice with donor alloantigen combined with anti-CD4 antibody therapy generates CD25+CD4+ T cells that can prevent graft rejection. We therefore used this sensitive adoptive transfer mouse model to ask whether blood transfusion in the absence of any other treatment can also lead to the generation of alloreactive CD25+CD4+ regulatory T cells. Results: Although a single donor-specific transfusion (DST) fails to induce dominant regulation, we demonstrate that pretreatment with multiple DSTs generates CD25+CD4+ T cells that are as effective as those that result from blood transfusion under anti-CD4 antibody cover. More importantly, our results show that these cells also develop following multiple transfusions of unrelated (random) blood. Conclusion: These results provide a basis for understanding the blood-transfusion effect in transplantation and, by providing a link between naturally occurring regulatory cells and those induced by alloantigen, may shed new light on the fundamental basis of the effect itself.
MeSH term(s)	Animals ; Blood Transfusion ; CD4-Positive T-Lymphocytes/immunology ; Graft Survival/immunology ; Isoantigens/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Receptors, Interleukin-2/analysis ; Transplantation Immunology
Chemical Substances	Isoantigens ; Receptors, Interleukin-2
Language	English
Publishing date	2003-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/01.TP.0000083043.84630.99
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Article: CD25+CD4+ regulatory T cells develop in mice not only during spontaneous acceptance of liver allografts but also after acute allograft rejection.

Steger, Ulrich / Kingsley, Cherry I / Karim, Mahzuz / Bushell, Andrew R / Wood, Kathryn J

Transplantation

2006 Volume 82, Issue 9, Page(s) 1202–1209

Abstract: Background: Liver grafts transplanted across a major histocompatibility barrier are accepted spontaneously and induce donor specific tolerance in some species. Here, we investigated whether liver allograft acceptance is characterized by, and depends ... ...

Abstract	Background: Liver grafts transplanted across a major histocompatibility barrier are accepted spontaneously and induce donor specific tolerance in some species. Here, we investigated whether liver allograft acceptance is characterized by, and depends upon, the presence of donor reactive CD25CD4 regulatory T cells. Methods: CD25 and CD25CD4 T cells, isolated from CBA. Ca (H2) recipients of C57BL/10 (B10; H2) liver and heart allografts 10 days after transplantation, were transferred into CBA. Rag1 mice to investigate their influence on skin allograft rejection mediated by CD45RBCD4 effector T Cells. Results: Fully allogeneic B10 liver allografts were spontaneously accepted by naive CBA.Ca recipient mice, whereas B10 cardiac allografts were acutely rejected (mean survival time=7 days). Strikingly, however, CD25CD4 T cells isolated from both liver and cardiac allograft recipients were able to prevent skin allograft rejection in this adoptive transfer model. Interestingly, CD25CD4 T cells isolated from liver graft recipients also showed suppressive potency upon adoptive transfer. Furthermore, depletion of CD25CD4 T cells in primary liver allograft recipients did not prevent the acceptance of a secondary donor-specific skin graft. Conclusions: Our data provide evidence that the presence of CD25CD4 regulatory T cells is not a unique feature of allograft acceptance and is more likely the result of sustained exposure to donor alloantigens in vivo.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; CD4 Antigens/analysis ; Graft Rejection/immunology ; Graft Survival/immunology ; Heart Transplantation ; Interleukin-2 Receptor alpha Subunit/analysis ; Interleukin-2 Receptor alpha Subunit/antagonists & inhibitors ; Liver Transplantation/immunology ; Lymphocyte Activation ; Lymphocyte Depletion ; Mice ; Mice, Inbred Strains ; Skin Transplantation/immunology ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; Transplantation Tolerance
Chemical Substances	Antibodies, Monoclonal ; CD4 Antigens ; Interleukin-2 Receptor alpha Subunit
Language	English
Publishing date	2006-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/01.tp.0000235913.58337.b4
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Article: CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses.

Kingsley, Cherry I / Karim, Mahzuz / Bushell, Andrew R / Wood, Kathryn J

Journal of immunology (Baltimore, Md. : 1950)

2002 Volume 168, Issue 3, Page(s) 1080–1086

Abstract: Specific and selective immunological unresponsiveness to donor alloantigens can be induced in vivo. We have shown previously that CD25+CD4+ T cells from mice exhibiting long-term operational tolerance to donor alloantigens can regulate rejection of ... ...

Abstract	Specific and selective immunological unresponsiveness to donor alloantigens can be induced in vivo. We have shown previously that CD25+CD4+ T cells from mice exhibiting long-term operational tolerance to donor alloantigens can regulate rejection of allogeneic skin grafts mediated by CD45RB(high)CD4+ T cells. In this study, we wished to determine whether donor-specific regulatory cells can be generated during the induction phase of unresponsiveness, i.e., before transplantation. We provide evidence that pretreatment with anti-CD4 Ab plus a donor-specific transfusion generates donor-specific regulatory CD25+CD4+ T cells that can suppress rejection of skin grafts mediated by naive CD45RB(high)CD4+ T cells. Regulatory cells were contained only in the CD25+ fraction, as equivalent numbers of CD25-CD4+ T cells were unable to regulate rejection. This pretreatment strategy led to increased expression of CD122 by the CD25+CD4+ T cells. Blockade of both the IL-10 and CTLA-4 pathways abrogated immunoregulation mediated by CD25+ T cells, suggesting that IL-10 and CTLA-4 are required for the functional activity of this population of immunoregulatory T cells. In clinical transplantation, the generation of regulatory T cells that could provide dynamic control of rejection responses is a possible route to permanent graft survival without the need for long-term immunosuppression.
MeSH term(s)	Abatacept ; Animals ; Antibodies, Monoclonal/analysis ; Antigens, CD ; Antigens, Differentiation/biosynthesis ; Antigens, Differentiation/physiology ; Blood Transfusion ; CD4 Antigens/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/transplantation ; CTLA-4 Antigen ; Epitopes, T-Lymphocyte/immunology ; Graft Rejection/immunology ; Graft Rejection/prevention & control ; Immunoconjugates ; Interleukin-10/physiology ; Isoantigens/immunology ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Mice, Knockout ; Receptors, Interleukin-2/biosynthesis ; Receptors, Interleukin-2/physiology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocyte Subsets/transplantation ; Transplantation Conditioning ; Transplantation Tolerance
Chemical Substances	Antibodies, Monoclonal ; Antigens, CD ; Antigens, Differentiation ; CD4 Antigens ; CTLA-4 Antigen ; Ctla4 protein, mouse ; Epitopes, T-Lymphocyte ; Immunoconjugates ; Isoantigens ; Receptors, Interleukin-2 ; Interleukin-10 (130068-27-8) ; Abatacept (7D0YB67S97)
Language	English
Publishing date	2002-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.168.3.1080
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Article: IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo.

Sawitzki, Birgit / Kingsley, Cherry I / Oliveira, Vanessa / Karim, Mahzuz / Herber, Manuela / Wood, Kathryn J

The Journal of experimental medicine

2005 Volume 201, Issue 12, Page(s) 1925–1935

Abstract: The significance of cytokine production by CD4(+) regulatory T (T reg) cells after antigen exposure in vivo and its impact on their regulatory activity remains unclear. Pretreatment with donor alloantigen under the cover of anti-CD4 therapy generates ... ...

Abstract	The significance of cytokine production by CD4(+) regulatory T (T reg) cells after antigen exposure in vivo and its impact on their regulatory activity remains unclear. Pretreatment with donor alloantigen under the cover of anti-CD4 therapy generates alloantigen reactive T reg cells that can prevent rejection of donor-specific skin grafts that are mediated by naive CD45RB(high)CD4(+) T cells. To examine the kinetics and importance of cytokine gene transcription by such alloantigen-reactive T reg cells, pretreated mice were rechallenged with donor alloantigen in vivo. CD25(+)CD4(+) T cells, but not CD25(-)CD4(+) T cells, showed a fivefold increase in IFN-gamma mRNA expression within 24 h of re-encountering alloantigen in vivo. This expression kinetic was highly antigen-specific and was of functional significance. Neutralizing IFN-gamma at the time of cotransfer of alloantigen reactive T reg cells, together with CD45RB(high)CD4(+) effector T cells into Rag(-/-) skin graft recipients, resulted in skin graft necrosis in all recipients; the generation and function of alloantigen-reactive T reg cells was impaired dramatically in IFN-gamma-deficient mice. These data support a unique role for IFN-gamma in the functional activity of alloantigen-reactive T reg cells during the development of operational tolerance to donor alloantigens in vivo.
MeSH term(s)	Analysis of Variance ; Animals ; Antibodies, Monoclonal/immunology ; CD4 Antigens/metabolism ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Interferon-gamma/metabolism ; Isoantigens/immunology ; Leukocyte Common Antigens/metabolism ; Mice ; Mice, Knockout ; Oligonucleotides ; RNA, Messenger/metabolism ; Receptors, Interleukin-2/metabolism ; Skin Transplantation/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/physiology ; Transcription, Genetic/immunology
Chemical Substances	Antibodies, Monoclonal ; CD4 Antigens ; Isoantigens ; Oligonucleotides ; RNA, Messenger ; Receptors, Interleukin-2 ; Interferon-gamma (82115-62-6) ; Leukocyte Common Antigens (EC 3.1.3.48)
Language	English
Publishing date	2005-06-20
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20050419
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Article ; Online: Intergenus F1-hybrids of African weakly electric fish (Mormyridae: Gnathonemus petersii ♂ × Campylomormyrus compressirostris ♀) are fertile

Korniienko, Yevheniia / Nzimora, Kingsley C. / Vater, Marianne / Tiedemann, Ralph / Kirschbaum, Frank

J Comp Physiol A. 2022 May, v. 208, no. 3 p.355-371

2022

Abstract: Hybridisation is an important element of adaptive radiation in fish but data are limited in weakly electric mormyrid fish in this respect. Recently, it has been shown that intragenus hybrids (Campylomormyrus) are fertile and are able to produce F2-fish. ... ...

Abstract	Hybridisation is an important element of adaptive radiation in fish but data are limited in weakly electric mormyrid fish in this respect. Recently, it has been shown that intragenus hybrids (Campylomormyrus) are fertile and are able to produce F2-fish. In this paper, we demonstrate that even intergenus hybrids (Gnathonemus petersii ♂ × Campylomormyrus compressirostris ♀) are fertile. Three artificial reproduction (AR) trials, with an average fertilisation rate of ca. 23%, yielded different numbers of survivals (maximally about 50%) of the F1-hybrids. The complete ontogenetic development of these hybrids is described concerning their morphology and electric organ discharge (EOD). Two EOD types emerged at the juvenile stage, which did not change up to adulthood. Type I consisted of four phases and Type II was triphasic. The minimum body length at sexual maturity was between 10 and 11 cm. Malformations, growth and mortality rates are also described.
Keywords	Campylomormyrus compressirostris ; Gnathonemus petersii ; adaptive radiation ; adulthood ; body length ; fish ; hybridization ; juveniles ; mortality ; ontogeny ; sexual maturity
Language	English
Dates of publication	2022-05
Size	p. 355-371.
Publishing place	Springer Berlin Heidelberg
Document type	Article ; Online
ZDB-ID	231244-x
ISSN	1432-1351 ; 0340-7594
ISSN (online)	1432-1351
ISSN	0340-7594
DOI	10.1007/s00359-022-01542-5
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Article: Alloantigen-induced CD25+CD4+ regulatory T cells can develop in vivo from CD25-CD4+ precursors in a thymus-independent process.

Karim, Mahzuz / Kingsley, Cherry I / Bushell, Andrew R / Sawitzki, Birgit S / Wood, Kathryn J

Journal of immunology (Baltimore, Md. : 1950)

2003 Volume 172, Issue 2, Page(s) 923–928

Abstract: The capacity of naturally occurring autoreactive CD25+CD4+ regulatory T cells (Treg) to control immune responses both in vivo and in vitro is now well established. It has been demonstrated that these cells undergo positive selection within the thymus and ...

Abstract	The capacity of naturally occurring autoreactive CD25+CD4+ regulatory T cells (Treg) to control immune responses both in vivo and in vitro is now well established. It has been demonstrated that these cells undergo positive selection within the thymus and appear to enter the periphery as committed CD25+CD4+ Treg. We have shown previously that CD25+CD4+ Treg with the capacity to prevent skin allograft rejection can be generated by pretreatment with donor alloantigen under the cover of anti-CD4 therapy. Here we demonstrate that this process does not require an intact thymus. Furthermore, generation of these Treg is not dependent on the expansion of CD25+CD4+ thymic emigrants, because depletion of CD25+ cells before pretreatment does not prevent Treg development, and Treg can be generated from CD25-CD4+ precursors. Taken together, these results clearly demonstrate that CD25+CD4+ Treg can be generated in the periphery from CD25-CD4+ precursors in a pathway distinct to that by which naturally occurring autoreactive CD25+CD4+ Treg develop. These observations may have important implications for the design of protocols, both experimental and clinical, for the induction of tolerance to autoantigens or alloantigens in adults with limited thymic function.
MeSH term(s)	Animals ; Antibodies, Monoclonal/administration & dosage ; Blood Transfusion ; CD4-Positive T-Lymphocytes/cytology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/transplantation ; Cell Differentiation/immunology ; Cell Movement/immunology ; Isoantigens/administration & dosage ; Isoantigens/biosynthesis ; Isoantigens/physiology ; Lymphocyte Depletion ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Mice, Knockout ; Receptors, Interleukin-2/administration & dosage ; Receptors, Interleukin-2/biosynthesis ; Receptors, Interleukin-2/immunology ; Skin Transplantation/immunology ; Stem Cells/cytology ; Stem Cells/immunology ; Stem Cells/metabolism ; T-Lymphocyte Subsets/cytology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocyte Subsets/transplantation ; Thymus Gland/cytology ; Thymus Gland/immunology ; Thymus Gland/metabolism
Chemical Substances	Antibodies, Monoclonal ; Isoantigens ; Receptors, Interleukin-2
Language	English
Publishing date	2003-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.172.2.923
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Article ; Online: Intergenus F1-hybrids of African weakly electric fish (Mormyridae: Gnathonemus petersii ♂ × Campylomormyrus compressirostris ♀) are fertile.

Korniienko, Yevheniia / Nzimora, Kingsley C / Vater, Marianne / Tiedemann, Ralph / Kirschbaum, Frank

Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology

2022 Volume 208, Issue 3, Page(s) 355–371

Abstract	Hybridisation is an important element of adaptive radiation in fish but data are limited in weakly electric mormyrid fish in this respect. Recently, it has been shown that intragenus hybrids (Campylomormyrus) are fertile and are able to produce F2-fish. In this paper, we demonstrate that even intergenus hybrids (Gnathonemus petersii ♂ × Campylomormyrus compressirostris ♀) are fertile. Three artificial reproduction (AR) trials, with an average fertilisation rate of ca. 23%, yielded different numbers of survivals (maximally about 50%) of the F1-hybrids. The complete ontogenetic development of these hybrids is described concerning their morphology and electric organ discharge (EOD). Two EOD types emerged at the juvenile stage, which did not change up to adulthood. Type I consisted of four phases and Type II was triphasic. The minimum body length at sexual maturity was between 10 and 11 cm. Malformations, growth and mortality rates are also described.
MeSH term(s)	Animals ; Electric Fish/physiology ; Electric Organ/physiology ; Fertility ; Hybridization, Genetic
Language	English
Publishing date	2022-02-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120907-3
ISSN	1432-1351 ; 0302-9824 ; 0373-0859 ; 0340-7594
ISSN (online)	1432-1351
ISSN	0302-9824 ; 0373-0859 ; 0340-7594
DOI	10.1007/s00359-022-01542-5
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Article ; Online: Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study.

Flower, Barnaby / Hung, Le Manh / Mccabe, Leanne / Ansari, M Azim / Le Ngoc, Chau / Vo Thi, Thu / Vu Thi Kim, Hang / Nguyen Thi Ngoc, Phuong / Phuong, Le Thanh / Quang, Vo Minh / Dang Trong, Thuan / Le Thi, Thao / Nguyen Bao, Tran / Kingsley, Cherry / Smith, David / Hoglund, Richard M / Tarning, Joel / Kestelyn, Evelyne / Pett, Sarah L /

van Doorn, Rogier / Van Nuil, Jennifer Ilo / Turner, Hugo / Thwaites, Guy E / Barnes, Eleanor / Rahman, Motiur / Walker, Ann Sarah / Day, Jeremy N / Chau, Nguyen V V / Cooke, Graham S

eLife

2023 Volume 12

Abstract: Background: World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological ...

Abstract	Background: World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome. Methods: Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4- or 8-week treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on days 0 and 28. Results: Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and 1 withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall, 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance-associated substitutions (RASs), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS, SOF or DCV levels. Conclusions: Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use in patients with mild liver disease, while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4-week treatment. Funding: Funded by the Medical Research Council (Grant MR/P025064/1) and The Global Challenges Research 70 Fund (Wellcome Trust Grant 206/296/Z/17/Z).
MeSH term(s)	Adult ; Humans ; Sofosbuvir/therapeutic use ; Antiviral Agents ; Pilot Projects ; Hepatitis C, Chronic/drug therapy ; Drug Therapy, Combination ; Hepatitis C ; Treatment Outcome ; Hepacivirus/genetics ; Genotype ; Ribavirin/therapeutic use ; Interleukins/genetics
Chemical Substances	Sofosbuvir (WJ6CA3ZU8B) ; Antiviral Agents ; daclatasvir (LI2427F9CI) ; Ribavirin (49717AWG6K) ; IFNL4 protein, human ; Interleukins
Language	English
Publishing date	2023-01-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.81801
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Article: The ICOS molecule plays a crucial role in the development of mucosal tolerance.

Miyamoto, Katsuichi / Kingsley, Cherry I / Zhang, Xingmin / Jabs, Claudia / Izikson, Leonid / Sobel, Raymond A / Weiner, Howard L / Kuchroo, Vijay K / Sharpe, Arlene H

Journal of immunology (Baltimore, Md. : 1950)

2005 Volume 175, Issue 11, Page(s) 7341–7347

Abstract: The ICOS molecule stimulates production of the immunoregulatory cytokine IL-10, suggesting an important role for ICOS in controlling IL-10-producing regulatory T cells and peripheral T cell tolerance. In this study we investigate whether ICOS is required ...

Abstract	The ICOS molecule stimulates production of the immunoregulatory cytokine IL-10, suggesting an important role for ICOS in controlling IL-10-producing regulatory T cells and peripheral T cell tolerance. In this study we investigate whether ICOS is required for development of oral, nasal, and high dose i.v. tolerance. Oral administration of encephalitogenic myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to ICOS-deficient (ICOS-/-) mice did not inhibit experimental autoimmune encephalomyelitis (EAE), T cell proliferation, or IFN-gamma production, in striking contrast to wild-type mice. Similarly, intranasal administration of MOG(35-55) before EAE induction suppressed EAE and T cell responses in wild-type, but not in ICOS-/-, mice. In contrast, ICOS-/- mice were as susceptible as wild-type mice to high dose tolerance. These results indicate that ICOS plays an essential and specific role in mucosal tolerance and that distinct costimulatory pathways differentially regulate different forms of peripheral tolerance. Surprisingly, CD4+ cells from MOG-fed wild-type and ICOS-/- mice could transfer suppression to wild-type recipients, indicating that functional regulatory CD4+ cells can develop in the absence of ICOS. However, CD4+ T cells from MOG-fed wild-type mice could not transfer suppression to ICOS-/- recipients, suggesting that ICOS may have a key role in controlling the effector functions of regulatory T cells. These results suggest that stimulating ICOS may provide an effective therapeutic approach for promoting mucosal tolerance.
MeSH term(s)	Administration, Intranasal ; Administration, Oral ; Adoptive Transfer ; Animals ; Antigens, Differentiation, T-Lymphocyte/immunology ; Antigens, Differentiation, T-Lymphocyte/metabolism ; Cytokines/immunology ; Cytokines/metabolism ; Dose-Response Relationship, Drug ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Glycoproteins/administration & dosage ; Glycoproteins/immunology ; Immune Tolerance/immunology ; Immunity, Mucosal/immunology ; Inducible T-Cell Co-Stimulator Protein ; Injections, Intravenous ; Mice ; Myelin-Oligodendrocyte Glycoprotein ; Peptide Fragments/administration & dosage ; Peptide Fragments/immunology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Antigens, Differentiation, T-Lymphocyte ; Cytokines ; Glycoproteins ; Icos protein, mouse ; Inducible T-Cell Co-Stimulator Protein ; Myelin-Oligodendrocyte Glycoprotein ; Peptide Fragments ; myelin oligodendrocyte glycoprotein (35-55)
Language	English
Publishing date	2005-10-23
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.175.11.7341
Database	MEDical Literature Analysis and Retrieval System OnLINE

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