Induction Therapy With Monoclonal Antibodies Specific for Cd80 and Cd86 Delays the Onset of Acute Renal Allograft Rejection in Non-Human Primates1

Kirk, Allan D.; Tadaki, Douglas K.; Celniker, Abbie; Batty, D. Scott; Berning, Justin D.; Colonna, John O.; Cruzata, Francis; Elster, Eric A.; Gray, Gary S.; Kampen, Robert L.; Patterson, Noelle B.; Szklut, Pamela; Swanson, J.L.; Xu, He; Harlan, David M.

doi:10.1097/00007890-200108150-00005

Cited by 131 publications

(68 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Alternatively, CD4 blockade could result in suboptimal T cell stimulation upon APC engagement leading to tolerance induction. This idea is supported by the fact that different studies demonstrated tolerance induction after blockade of other co-stimulatory molecules, such as CD28, CD80, or CD86 (38,43,44).…”

Section: /Cd8mentioning

confidence: 92%

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

et al. 2016

View full text Add to dashboard Cite

NOD.Cg-Prkdcscid IL-2rg tm1Wjl /SzJ (NSG) mice are a valuable tool for studying Graftversus-Host-Disease (GvHD) induced by human immune cells. We used a model of acute GvHD by transfer of human peripheral blood mononuclear cells (PBMCs) into NSG mice. The severity of GvHD was reflected by weight loss and was associated with engraftment of human cells and the expansion of leukocytes, particularly granulocytes and monocytes. Pre-treatment of PBMCs with the anti-human CD4 antibody MAX.16H5 IgG1 or IgG4 attenuated GvHD. The transplantation of 2 3 10 7 PBMCs without anti-human CD4 pre-treatment induced a severe GvHD (0% survival). In animals receiving 2 3 10 7 PBMCs pre-incubated with MAX.16H5 IgG1 or IgG4, GvHD development was reduced and survival was increased. Immune reconstitution was measured by flow cytometry and confirmed for human leukocytes (CD45), CD3 /CD41 T helper cells. Human B cells (CD19) and monocytes (CD14) could not be detected. Histopathological analysis (TUNEL assay) of the gut of recipient animals showed significantly less apoptotic crypt cells in animals receiving a MAX.16H5 IgG1 pre-incubated graft. These findings indicate that preincubation of an allogeneic graft with an anti-human CD4 antibody may decrease the frequency and severity of GvHD after hematopoietic stem cell transplantation (HSCT) and the need of conventional immunosuppressive drugs. Moreover, this approach most probably provides a safer HSCT that must be confirmed in appropriate clinical trials in the future. V C 2016 International Society for Advancement of Cytometry

show abstract

Section: /Cd8mentioning

confidence: 92%

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…by our group and others (10)(11)(12)(13)(14)(15)(16). Belatacept is a first-in-class selective costimulation blocker and is clinically indicated as a CNI inhibitor substitute with mycophenolate mofetil and steroids after renal transplantation.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus to Belatacept Conversion Following Hand Transplantation: A Case Report.

et al. 2014

View full text Add to dashboard Cite

Vascularized composite allotransplantation (VCA) has emerged as a viable limb replacement strategy for selected patients with upper limb amputation. However, allograft rejection has been seen in essentially all reported VCA recipients indicating a requirement for substantial immunosuppressive therapy. Calcineurin inhibitors have served as the centerpiece agent in all reported cases, and CNI-associated complications associated with the broad therapeutic effects and side effects of calcineurin inhibitors have been similarly common. Recently, belatacept has been approved as a calcineurin inhibitor replacement in kidney transplantation, but to date, its use in VCA has not been reported. Herein, we report on the case of a hand transplant recipient who developed recurrent acute rejection with alloantibody formation and concomitant calcineurin inhibitor nephrotoxicity, all of which resolved upon conversion from a maintenance regimen of tacrolimus, mycophenolate mofetil and steroids to belatacept and sirolimus. This case indicates that belatacept may be a reasonable maintenance immunosuppressive alternative for use in VCA, providing sufficient prophylaxis from rejection with a reduced side effect profile, the latter being particularly relevant for nonlife threatening conditions typically treated by VCA.

show abstract

“…The efficacy of monoclonal antibodies against CD80 and CD86 was investigated in the NHP renal allograft model (Kirk et al 2001b). Monotherapy with either of these antibodies produced only modest increases in time to rejection.…”

Section: Costimulation Blockadementioning

confidence: 99%

Induction of transplantation tolerance in non-human primate preclinical models

Hale

Dhanireddy

Bruno

et al. 2005

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

Short-term outcomes following organ transplantation have improved considerably since the availability of cyclosporine ushered in the modern era of immunosuppression. In spite of this, many of the current limitations to progress in the field are directly related to the existing practice of relatively non-specific immunosuppression. These include increased risks of opportunistic infection and cancer, and toxicity associated with long-term immunosuppressive drug exposure. In addition, long-term graft loss continues to result in part from a failure to adequately control the anti-donor immune response. The development of a safe and reliable means of inducing tolerance would ameliorate these issues and improve the lives of transplant recipients, yet given the improving clinical standard of care, the translation of new therapies has become appropriately more cautious and dependent on increasingly predictive preclinical models. While convenient and easy to use, rodent tolerance models have not to date been reliably capable of predicting a therapy's potential efficacy in humans. Non-human primates possess an immune system that more closely approximates that found in humans, and have served as a more rigorous preclinical testing ground for novel therapies. Prior to clinical adaptation therefore, tolerance regimens should be vetted in non-human primates to ensure that there is sufficient potential for efficacy to justify the risk of its application.

show abstract

Induction Therapy With Monoclonal Antibodies Specific for Cd80 and Cd86 Delays the Onset of Acute Renal Allograft Rejection in Non-Human Primates1

Cited by 131 publications

References 23 publications

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

Tacrolimus to Belatacept Conversion Following Hand Transplantation: A Case Report.

Induction of transplantation tolerance in non-human primate preclinical models

Contact Info

Product

Resources

About

Induction Therapy With Monoclonal Antibodies Specific for Cd80 and Cd86 Delays the Onset of Acute Renal Allograft Rejection in Non-Human Primates1

Cited by 131 publications

References 23 publications

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ−/− (NSG) mice by ex vivo modulation of human CD4+ T cells

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ−/− (NSG) mice by ex vivo modulation of human CD4+ T cells

Tacrolimus to Belatacept Conversion Following Hand Transplantation: A Case Report.

Induction of transplantation tolerance in non-human primate preclinical models

Contact Info

Product

Resources

About

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells