Treatment with humanized monoclonal antibodies against CD80 and CD86 combined with sirolimus prolongs renal allograft survival in cynomolgus monkeys1

Bı̂rsan, Tudor; Hausen, Bernard; Higgins, Julian P T; Hubble, Richard W; Klupp, J; Stalder, Mario; Celniker, Abbie; Friedrich, Stuart; O'Hara, R M; Morris, Randall E.

doi:10.1097/01.tp.0000066806.10029.7a

Cited by 41 publications

(25 citation statements)

References 34 publications

(44 reference statements)

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“…There have been attempts to utilize NPs that combine antigen and immunesuppressive agents such as rapamycin to alter DC phenotype in vivo and potentially induce tolerance [5,6,9]. Rapamycin has been known for over two decades to have 'tolerogenic' effects when combined with antigen [91,92] and the adoptive transfer of rapamycin-treated DCs can promote the long-term survival of skin grafts in rodent transplant recipients [93]. In the context of NPs, Haddadi and colleagues showed that rapamycin-loaded PLGA NPs preferentially bound to DCs and induced an immature 'tolerogenic' phenotype [61].…”

Section: Np Development For Tolerancementioning

confidence: 99%

Harnessing Nanoparticles for Immune Modulation

Getts¹,

Shea²,

Miller³

et al. 2016

Trends in Immunology

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Recent approaches using nanoparticles engineered for immune regulation have yielded promising results in preclinical models of disease. The number of nanoparticle therapies is growing, fueled by innovations in nanotechnology and advances in understanding of the underlying pathogenesis of immune-mediated diseases. In particular, recent mechanistic insight into the ways in which nanoparticles interact with the mononuclear phagocyte system and impact its function during homeostasis and inflammation have highlighted the potential of nanoparticle-based therapies for controlling severe inflammation while concurrently restoring peripheral immune tolerance in autoimmune disease. Here we review recent advances in nanoparticle-based approaches aimed at immune-modulation, and discuss these in the context of concepts in polymeric nanoparticle development, including particle modification, delivery and the factors associated with successful clinical deployment.

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Section: Np Development For Tolerancementioning

confidence: 99%

Harnessing Nanoparticles for Immune Modulation

Getts¹,

Shea²,

Miller³

et al. 2016

Trends in Immunology

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“…Prevention of costimulation can result in clonal anergy (Baliga et al 1994). Co-stimulatory blockade has been shown to prolong allograft survival in different transplant models (Adams et al 2002;Birsan et al 2003;Kirk et al 1999). …”

Section: Co-stimulation Blockade and Transplantationmentioning

confidence: 98%

Nonhuman Primate Models for Islet Transplantation in Type 1 Diabetes Research

Gaur¹

2004

ILAR Journal

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Insulin-dependent diabetes mellitus is an autoimmune disease that causes a progressive destruction of the pancreatic beta cells. As a result, the patient requires exogenous insulin to maintain normal blood glucose levels. Both the pancreas and the islets of Langerhans have been transplanted successfully in humans and in animal models, resulting in full normalization of glucose homeostasis. However, insulin independence, transient or persistent, was documented in only a small fraction of cases until recently. The chronic immunosuppression required to avoid immunological rejection appears to be toxic to the islets and adds the risk of lymphoproliferative disease reported earlier. For islet transplantation to become the method of choice, it is essential first to identify islet-friendly immunosuppressive regimens and/or to develop methods that induce donor-specific tolerance and improve islet isolation and transplantation protocols. Indeed, researchers have already successfully allografted islets in the presence of nonsteroidal immunosuppression in a process known as the Edmonton protocol. An alternative method, gene therapy, could replace these other methods and better meet the insulin requirement of an individual without requiring pancreatic or islet transplantation. This alternative, however, requires animal models to develop and test clinical protocols and to demonstrate the feasibility of preclinical trials. Nonhuman primates are ideally suited to achieve these goals. The efforts toward developing a nonhuman primate diabetic model with demonstrable insulin dependence are discussed and include pancreatic and islet transplant trials to reverse the diabetic state and achieve insulin independence. Also described are the various protocols that have been tested in primates to circumvent immunosuppression by using tolerance induction strategies in lieu of immunosuppression, thus exploring the field of donor-specific tolerance that extends beyond islet transplantation.

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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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Treatment with humanized monoclonal antibodies against CD80 and CD86 combined with sirolimus prolongs renal allograft survival in cynomolgus monkeys1

Abstract: Sirolimus can be successfully combined with humanized mAb against CD80 and CD86. Induction with a short course of mAb is effective in prolonging allograft survival in combination with sirolimus.

Cited by 41 publications

References 34 publications

Harnessing Nanoparticles for Immune Modulation

Harnessing Nanoparticles for Immune Modulation

Nonhuman Primate Models for Islet Transplantation in Type 1 Diabetes Research

Primate Models in Organ Transplantation

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