Costimulation Blockade in Non-human Primate Renal Allotransplantation

Kirk, Allan D.; Harlan, David M.; Burkly, Linda C.; Gray, Gary S.; Batty, D. Scott; Berning, Justin D.; Colonna, John O.; Fechner, John H.; Germond, Rhonda L.; Hyde, Jeffery P.; Kampen, Robert L.; Patterson, Noelle B.; Tadaki, Douglas K.; Knechtle, Stuart J.

doi:10.1097/00007890-199810270-00053

Cited by 3 publications

(2 citation statements)

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“…An anti-CD40L ab (also named anti-CD154 ab) was successfully used preclinically (reviewed in Shu et al, 10 even clinically after renal transplantation), but its thrombotic side effects prevent clinical use. 93 New nonthrombogenic versions are in development and testing, including a novel chimeric anti-CD154 ab 94 and a PASylated humanized anti-CD154 Fab. 95 In this context, one should consider the distribution of CD40 and its ligand on cells involved in xenogeneic rejection.…”

Section: Clinical Cardiac Xenotransplantationmentioning

confidence: 99%

Pathways to Clinical Cardiac Xenotransplantation

Reichart¹,

Längin

Denner

et al. 2021

Transplantation

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Heart transplantation is the only long-lasting lifesaving option for patients with terminal cardiac failure. The number of available human organs is however far below the actual need, resulting in substantial mortality of patients while waiting for a human heart. Mechanical assist devices are used to support cardiac function but are associated with a high risk of severe complications and poor quality of life for the patients. Consistent success in orthotopic transplantation of genetically modified pig hearts into baboons indicates that cardiac xenotransplantation may become a clinically applicable option for heart failure patients who cannot get a human heart transplant. In this overview, we project potential paths to clinical cardiac xenotransplantation, including the choice of genetically modified source pigs; associated requirements of microbiological, including virological, safety; optimized matching of source pig and recipient; and specific treatments of the donor heart after explantation and of the recipients. Moreover, selection of patients and the regulatory framework will be discussed.

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Section: Clinical Cardiac Xenotransplantationmentioning

confidence: 99%

Pathways to Clinical Cardiac Xenotransplantation

Reichart¹,

Längin

Denner

et al. 2021

Transplantation

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“…For example, blockade of the CD28 pathway can ameliorate the symptoms of experimental autoimmune encephalitis, a mouse autoimmune disease that attacks the central nervous system and is mediated primarily by CD4 ϩ T cells (10). In the transplant community, great interest has been generated by the observation that simultaneous blockade of the CD40 and CD28 costimulatory pathways significantly prolongs allograft survival in both mice and primates in the absence of further immunosuppression (11,12). Furthermore, blockade of either or both of these pathways has been a central component of several strategies aimed at inducing donor-specific tolerance (13)(14)(15).…”

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confidence: 99%

Genetic Characterization of Strain Differences in the Ability to Mediate CD40/CD28-Independent Rejection of Skin Allografts

Williams

Trambley

et al. 2000

The Journal of Immunology

128

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Simultaneous blockade of the CD40 and CD28 T cell costimulatory pathways effectively promotes skin allograft survival in C3H/HeJ mice, extending median survival times (MSTs) beyond 100 days. This strategy is markedly less effective in C57BL/6 mice, with MSTs ranging between 20 and 30 days. In this study, we investigate the underlying genetic causes of these distinct phenotypes. Using H-2 congenic mice, we show that the genetic basis for the varied responses between these two strains is independent of the H-2 locus and T cell precursor frequency. C57BL/6 mice treated with costimulation blockade are able to generate allospecific CTL- and IFN-γ-producing T cells within 3–4 wk posttransplant, whereas mice with a C3H background generate neither CTL- nor IFN-γ-producing cells. Thus, differences appear to be in the generation of the immune response and not T cell homing. Strain differences in costimulation blockade-induced hyporesponsiveness persist in the absence of CD4+ T cells, implying a direct effect on CD8+ T cells. We demonstrate that genetic differences are important in cells of hemopoietic origin and that the costimulation blockade-resistant phenotype is dominant. Analysis of BXH recombinant inbred strains indicates that multiple loci contribute to the phenotype, and that the blockade resistance loci are preliminarily linked to 17 markers on four chromosomes. We conclude that strain variation in allograft MSTs following CD40/CD28 blockade results from the ability of CD8+ T cells in some strains to use alternative modes of costimulation to mount an effective alloresponse.

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Coadministration of Either Cyclosporine or Steroids With Humanized Monoclonal Antibodies Against Cd80 and Cd86 Successfully Prolong Allograft Survival After Life Supporting Renal Transplantation in Cynomolgus Monkeys1

Hausen

Klupp

Christians³

et al. 2001

Transplantation

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Our data show that combining a calcineurin inhibitor or prednisone with mAbs designed to block costimulatory signals does not antagonize the immunosuppressive efficacy of these mAbs. In addition, combining CsA with mAbs directed against the CD80 and CD86 receptors significantly prolongs graft survival when compared to CsA monotherapy. Therefore clinical trials of humanized mAbs to CD80 and CD86 used in combination with conventional immunosuppression can be considered.

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Costimulation Blockade in Non-human Primate Renal Allotransplantation

Cited by 3 publications

References 0 publications

Pathways to Clinical Cardiac Xenotransplantation

Pathways to Clinical Cardiac Xenotransplantation

Genetic Characterization of Strain Differences in the Ability to Mediate CD40/CD28-Independent Rejection of Skin Allografts

Coadministration of Either Cyclosporine or Steroids With Humanized Monoclonal Antibodies Against Cd80 and Cd86 Successfully Prolong Allograft Survival After Life Supporting Renal Transplantation in Cynomolgus Monkeys1

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