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, Bernard; Klupp, J; Christians, Uwe; Higgins, Julian P T; Baumgartner, Roxanne E.; Hook, Laura; Friedrich, Stuart; Celnicker, Abbie; Morris, Randall E.

doi:10.1097/00007890-200109270-00025

Cited by 44 publications

(36 citation statements)

References 32 publications

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“…Because xenogeneic CMR is sensitive to CsA therapy, a novel therapy may easily be applied to larger animal nonhuman primate models of xenotransplantation. Anti-CD80/CD86 Ab therapy and CsA have already demonstrated efficacy in suppressing nonhuman primate and human immune responses (41). Shifting the immune response from CD86 to CD80, by neutralization of CD86, may alter the number of CD4 ϩ…”

Section: Discussionmentioning

confidence: 99%

CD80/CD86 Costimulation Regulates Acute Vascular Rejection

Hosiawa

Wang²,

DeVries

et al. 2005

The Journal of Immunology

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Xenotransplantation may provide the only solution to the shortage of human donor organs. Although hyperacute rejection associated with xenotransplantation can now be overcome, acute vascular rejection (AVR) remains a primary barrier to xenotransplantation. To date, standard immunosuppressive agents fail to block AVR or prolong xenograft survival. The present study was undertaken to determine the role of CD80/CD86 costimulatory molecules in regulating AVR. Lewis rat hearts were transplanted heterotopically into wild-type or IL-12, CD80- or CD86-deficient C57BL/6 mice. Wild-type recipients were treated with CD80 or CD86 neutralizing Ab with and without daily cyclosporin A (CsA, 15 mg/kg). Transplanted hearts in untreated wild-type recipients were rejected on postoperative days (POD) 17–21 and showed cell-mediated rejection (CMR) and AVR pathologies. In contrast, transplanted hearts in IL-12 and CD80 recipients or wild-type recipients treated with CD80 neutralizing Ab were rapidly rejected on POD 5 and 6 with AVR pathology. Interestingly, hearts transplanted into CD86 knockout recipients or wild-type recipients treated with CD86 neutralizing Ab underwent CMR on POD 17. Finally, blockade of CD86 but not CD80 rendered xenograft recipients sensitive to daily CsA therapy, leading to indefinite xenograft survival. To conclude, we demonstrate that AVR can be overcome by blocking the CD86 costimulatory pathway. Furthermore, we demonstrate that CD80 and CD86 have opposing roles in regulation of xenotransplantation rejection, where CD80 drives CMR and attenuates AVR while CD86 drives AVR. Most strikingly, indefinite xenograft survival can be achieved by suppressing AVR with CD86 neutralization in combination of CsA therapy, which inhibits CMR.

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Section: Discussionmentioning

confidence: 99%

CD80/CD86 Costimulation Regulates Acute Vascular Rejection

Hosiawa

Wang²,

DeVries

et al. 2005

The Journal of Immunology

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“…23 In another monkey model using anti-B7 mAbs, renal allograft survival was not inhibited by chronic steroid treatment and was even promoted by CyA administration. 24 In a rat model, FTY720 given at high doses prolonged cardiac allograft survival in recipients that were transfected with CTLA4Ig. 25 Tolerance induction through BMT with cobl relies at least in part on mechanisms other than those that lead to graft prolongation through cobl without BMT.…”

Section: Introductionmentioning

confidence: 99%

The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade

Blaha

Bigenzahn

Koporc

et al. 2003

Blood

166

174

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“…Early work to study blockade of the CD28 pathway involved monoclonal antibodies against the B7 ligands CD80 and CD86. Three groups showed prolongation of renal allograft survival using the antibodies 1F1 and 3D1 either alone or in combination with other immunosuppressants (Hausen et al 2001;Kirk et al 2001;Montgomery et al 2002b;Birsan et al 2003). Another group used different clones, B7-24 and 1G10, in rhesus skin and renal transplant models with modest success (Ossevoort et al 1998a,b).…”

Section: Costimulation Blockadementioning

confidence: 99%

Primate Models in Organ Transplantation

Anderson

Kirk

2013

Cold Spring Harbor Perspectives in Medicine

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Large animal models have long served as the proving grounds for advances in transplantation, bridging the gap between inbred mouse experimentation and human clinical trials. Although a variety of species have been and continue to be used, the emergence of highly targeted biologic-and antibody-based therapies has required models to have a high degree of homology with humans. Thus, the nonhuman primate has become the model of choice in many settings. This article will provide an overview of nonhuman primate models of transplantation. Issues of primate genetics and care will be introduced, and a brief overview of technical aspects for various transplant models will be discussed. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed.A nimal experimentation has long provided a rational basis for the translation of treatments and techniques from the bench to the bedside. In general, all first-in-human trials require preparative animal experimentation to allow patients to make truly informed decisions about their participation. Properly designed animal studies in relevant species provide the necessary background experience with a novel approach to reasonably anticipate the efficacy or, at the very least, safety of a planned intervention. As such, they serve as a foundation on which human trials can be ethically designed, particularly in fields such as immunology, in which the complexity of the interactions involved has prevented the development of any sufficiently predictive in vitro model. Although animal models are far superior to in vitro models in projecting the potential of an approach, it must be recognized that they do not mimic clinical transplantation precisely, and thus cannot be expected to forecast the ultimate experience in humans.The mouse model has formed the backbone of medical research and development for many years owing to the relative ease of breeding and genetic manipulation of the animals at a comparatively low cost. For immunology research, the mouse immune system offers sufficient homology for pathway determination and mechanistic studies, and indeed represents the ideal platform for this type of endeavor. In contrast, the large animal models (dog, pig, and primate) are significantly more expensive and, with the exception of inbred miniature swine (Sachs 1992;Mezrich et al. 2003), exhibit increased genetic diversity, making definitive mechanistic studies much more difficult, if not impossible. However, this complexity makes large animals suited to preclinical studies, in which the addition of often-unanticipated variables allows for the examination of practicality, safety, and generalized efficacy. In general, mice define pathways, and large animal models help establish whether a particular pathway's effect is suffi-

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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

Cited by 44 publications

References 32 publications

CD80/CD86 Costimulation Regulates Acute Vascular Rejection

CD80/CD86 Costimulation Regulates Acute Vascular Rejection

The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade

Primate Models in Organ Transplantation

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