Impact of donor immune cells in pancreatic islet transplantation

Carter, J.D.; Chen, M.; Ellett, Justin D.; Smith, Kellie M.; Nadler, Jerry L.; Yang, Zhaopeng

doi:10.1016/j.transproceed.2004.09.084

Cited by 3 publications

(2 citation statements)

References 9 publications

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“…This construct has shown efficacy in multiple disease models in which it was successfully used as an anti-inflammatory gene therapy approach. [18][19][20][21][22][23][24][25][26][27][28][29][30] Mice were treated at 6 weeks of age, which is very early in the development of the autoimmune process in this model in which sustained levels of anti-dsDNA IgG antibodies appear between 4 and 5 months of age. 11 The experiment was terminated at 7 months of age, which corresponds to a phase of active autoimmunity, but before terminal end stage disease for most mice.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17] AAV-IL-10 has now been used successfully as an anti-inflammatory gene therapy in many models, including endotoximia, 18 arthritis, 19,20 atherosclerosis, 21 experimental autoimmune orchitis, 22 experimental autoimmune uveitis, 23,24 chronic renal disease 25 and type 1 diabetes. [26][27][28][29] Interestingly, it has been shown in this latter model that the protective effect of IL-10 overexpression was mediated through the induction and mobilization of CD4 þ CD25 þ regulatory T cells (T R ). 30 These results indicated that in these largely inflammatory T H1 cell-mediated diseases, the immunosuppressive activity of IL-10 was dominant.…”

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confidence: 99%

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IL-10 regulation of lupus in the NZM2410 murine model

Blenman

Duan

et al. 2006

Laboratory Investigation

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Multiple studies have reported high levels of IL-10 in SLE patients and in murine models of lupus. IL-10 is a regulatory cytokine mainly produced by B cells, which use this cytokine to support their proliferation, and by myeloid cells, which use IL-10 to reduce proinflammatory responses. IL-10 is also produced by a subset of CD4+ T regulatory cells. Various manipulations of IL-10 levels with repeated administrations of anti-IL-10 neutralizing antibodies, genetic ablation or injections of recombinant cytokine have shown contradictory results, which is likely to reflect the opposite effects of this cytokine on the two major effector arms of lupus pathologenesis, namely B cells and inflammation. We have investigated the role of IL-10 in a novel congenic model of lupus, B6.Sle1.Sle2.Sle3 (B6.TC), which consists of the three NZM2410-derived SLE susceptibility loci combined on a C57BL/6 background. We first investigated in this model the source of elevated IL-10 and shown that it results from a larger number of CD4+ T cells producing the cytokine, and from a greatly increased B1-a cell pool, which is the main IL-10 producing compartment. We have then used AAV-mediated skeletal muscle gene delivery to overexpress IL-10 in young B6.TC mice and follow disease marker expression up to 7 months of age. We show here that continuous overexpression of low levels of IL-10 significantly delayed antinuclear auto-antibody production and decreased clinical nephritis. B cell phenotypes were largely unaffected, while T-cell activation was significantly reduced. This highlighted the pivotal role played by T-cell activation in this model, and suggested that this pathway could be effectively targeted for therapeutic interventions. These results also reinforce the notion that IL-10 exerts multiple functions and commend caution in equating high levels of IL-10 and increased pathogenesis in systemic autoimmunity.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

IL-10 regulation of lupus in the NZM2410 murine model

Blenman

Duan

et al. 2006

Laboratory Investigation

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Treatment of human disease by adeno-associated viral gene transfer

2006

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During the past decade, in vivo administration of viral gene transfer vectors for treatment of numerous human diseases has been brought from bench to bedside in the form of clinical trials, mostly aimed at establishing the safety of the protocol. In preclinical studies in animal models of human disease, adeno-associated viral (AAV) vectors have emerged as a favored gene transfer system for this approach. These vectors are derived from a replication-deficient, non-pathogenic parvovirus with a single-stranded DNA genome. Efficient gene transfer to numerous target cells and tissues has been described. AAV is particularly efficient in transduction of non-dividing cells, and the vector genome persists predominantly in episomal forms. Substantial correction, and in some instances complete cure, of genetic disease has been obtained in animal models of hemophilia, lysosomal storage disorders, retinal diseases, disorders of the central nervous system, and other diseases. Therapeutic expression often lasted for months to years. Treatments of genetic disorders, cancer, and other acquired diseases are summarized in this review. Vector development, results in animals, early clinical experience, as well as potential hurdles and challenges are discussed.

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Lessons on autoimmune diabetes from animal models

Yang

Santamaría

2006

Clinical Science

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T1DM (Type I diabetes mellitus) results from selective destruction of the insulin-producing beta-cells of the pancreas by the immune system, and is characterized by hyperglycaemia and vascular complications arising from suboptimal control of blood glucose levels. The discovery of animal models of T1DM in the late 1970s and early 1980s, particularly the NOD (non-obese diabetic) mouse and the BB (BioBreeding) diabetes-prone rat, had a fundamental impact on our ability to understand the genetics, aetiology and pathogenesis of this disease. NOD and BB diabetes-prone rats spontaneously develop a form of diabetes that closely resembles the human counterpart. Early studies of these animals quickly led to the realization that T1DM is caused by autoreactive T-lymphocytes and revealed that the development of T1DM is controlled by numerous polymorphic genetic elements that are scattered throughout the genome. The development of transgenic and gene-targeting technologies during the 1980s allowed the generation of models of T1DM of reduced genetic and pathogenic complexity, and a more detailed understanding of the immunogenetics of T1DM. In this review, we summarize the contribution of studies in animal models of T1DM to our current understanding of four fundamental aspects of T1DM: (i) the nature of genetic elements affording T1DM susceptibility or resistance; (ii) the mechanisms underlying the development and recruitment of pathogenic autoreactive T-cells; (iii) the identity of islet antigens that contribute to the initiation and/or progression of islet inflammation and beta-cell destruction; and (iv) the design of avenues for therapeutic intervention that are rooted in the knowledge gained from studies of animal models. Development of new animal models will ensure continued progress in these four areas.

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Impact of donor immune cells in pancreatic islet transplantation

Cited by 3 publications

References 9 publications

IL-10 regulation of lupus in the NZM2410 murine model

IL-10 regulation of lupus in the NZM2410 murine model

Treatment of human disease by adeno-associated viral gene transfer

Lessons on autoimmune diabetes from animal models

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