A LOW DONOR ISLET MASS IS SUFFICIENT TO RESTORE NORMOGLYCEMIA IN DIABETIC NOD MICE AFTER PRETRANSPLANT INDUCTION OF A SUBSTANTIAL LEVEL OF DONOR CHIMERISM
Bibliographic record
Abstract
O200 Aims: Two or more donors are required for a successful human islet allotransplantation under the current Edmonton protocol. However, human islet autotransplant recipients after pancreatectomy need fewer islets per recipient than the islet allotransplant recipients. In this study, we determined whether the islet mass required to reverse diabetes could be significantly reduced in spontaneously diabetic NOD mice after establishing a substantial level of donor lymphocyte chimerism, as compared with the islet mass required for successful allogeneic islet transplantation in immunosuppressed diabetic NOD mice. Methods: Fludarabine phosphate and cyclophosphamide were given at day -1. Donor BALB/c (H-2d) bone marrow cells (4x107) were transplanted into spontaneously diabetic NOD mice (H-2g7) at day 0. Anti-CD154 mAb were given from day 0 to day 14. Donor chimerism was measured by flow cytometric analysis before islet transplantation. Different numbers of BALB/c islets were transplanted under left kidney capsule of diabetic NOD mice with >40% donor lymphocyte chimerism at 3 weeks post-bone marrow transplantation. We also transplanted different numbers of islets into spontaneously diabetic NOD mice under immunosuppression comparable to the Edmonton protocol. Diabetic NOD mice were treated with ALS (0.3 ml) on day –1 and 0, and rapamycin (1 mg/kg/day) and low-dose tacrolimus (0.5 mg/kg/day) beginning on day –2. Results: At 3 weeks post-islet transplantation, diabetes was not reversed in any diabetic NOD mice that received 100 islets and immunosuppressants ALS, ramamycin, and tacrolimus (N=3). When 200 islets were transplanted into diabetic NOD mice under immunosuppressants ALS, ramamycin, and tacrolimus, only 16 % of recipient mice achieved normoglycemia (N=12). When the number of transplanted islets was further increased to 300 and 400 in the diabetic NOD mice under immunosuppression with ALS, ramamycin, and tacrolimus; the percentage of mice that achieved normoglycemia was increased to 50% (N=12) and 75% (N=8). However, in diabetic NOD mice with donor lymphocyte chimerism >40% before islet transplantation, 83% of mice reversed diabetes 3 weeks after receiving 100 donor islets (N=6). When the number of transplanted islets was increased to 200 (N=9), 300 (N=8), and 400 (N=8), all recipient mice achieved normoglycemia. Conclusions: Our results demonstrate that a high number of islets are required to reverse diabetes in spontaneously diabetic NOD mice under immunosuppression. However, a low islet number is sufficient to restore normoglycemia in diabetic NOD mice with a substantial level of donor chimerism. These data suggest that a small number of transplanted islets are sufficient to reverse diabetes in those diabetic NOD mice whose alloimmune response and autoimmune response were abrogated by pretransplant induction of a substantial level of donor chimerism.
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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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".