Development and application of a non-rejectable composite pancreatic islet allograft using indoleamine 2, 3 dioxygenase in a diabetic mouse model
Bibliographic record
Abstract
Success of transplantation of pancreatic islets as a promising therapeutic method for restoring efficient regulated insulin secretion in type 1 diabetes depends on lifelong use of immunosuppressive drugs. With the goal of eliminating the necessity of systemic immunosuppressive agents after islet transplantation, in this doctoral research project we hypothesized that a novel non-rejectable islet graft through employing a local immunosuppressive factor, indoleamine 2, 3 dioxygenase (IDO) can be developed and applied. IDO is a tryptophan degrading enzyme and functions as a potent immunomodulatory factor. To address this hypothesis, we engineered a three-dimensional composite islet graft equipped with IDO expressing bystander cells as local immunosuppressive system. In this composite graft, expression of IDO in syngeneic fibroblasts provided a low tryptophan microenvironment within which T-cells could not proliferate and infiltrate islets. Three specific aims were accomplished in this study. We first showed that local expression of IDO in syngeneic bystander fibroblasts efficiently suppressed in vitro proliferation of lymphocytes stimulated with allogeneic pancreatic islets. In the next phase, the impact of IDO on viability and function of mouse islets embedded within IDO-expressing fibroblast-populated collagen matrix was investigated. The result showed no reduction in islet cells viability and comparable insulin content and secretion in IDO-expressing versus control preparations. In contrast to lymphocytes, a nutrient deficiency stress-responsive pathway was not activated in islets co-cultured with IDO-expressing fibroblasts confirming the selective suppressive effect of IDO on immune versus islet cells. Furthermore, when allogeneic immune response was eliminated by using a syngeneic transplant model, IDO-expressing composite islet grafts were functional in vivo for up to 100 days. Finally, to address the last specific aim, composite allogeneic islet grafts were transplanted into renal subcapsular space of streptozotocin-induced diabetic immunocompetent mice. IDO-expressing grafts survived significantly longer than controls without using any systemic immunosuppressive agent (41.2±1.64 vs. 12.9±0.73 days, p<0.001). Local IDO expression evidently prevented lymphocyte infiltration into allografts and delayed alloantibody production. The findings presented in this thesis collectively prove the potent local immunosuppressive activity of IDO in islet allografts and set the stage for development of a long-lasting non-rejectable islet allograft using stable IDO induction in bystander fibroblasts.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".