Megadose Bone Marrow and Regulatory T cells for the Induction of Immune Tolerance in Non-Human Primates Through Durable Mixed Hematopoietic Chimerism Across MHC-barriers
Bibliographic record
Abstract
Introduction ?Mixed hematopoietic chimerism is a promising approach to achieving transplantation tolerance. Transient mixed chimerism (MC) leads to renal allograft tolerance in about 60% of Cynomolgus macaques (CM) when a donor kidney is co-transplanted with MHC-mismatched bone marrow (BMT). These findings are not recapitulated with other solid organs. The addition of regulatory T cells (Tregs) to BMT has promoted long-term MC and skin graft tolerance in mice. We aim to test the effect of high bone marrow dose and Treg administration with the hypothesis that these will enhance the duration and degree of donor MC in the CM model with the ultimate goal of inducing tolerance to any donor organ. Materials and Methods CM recipients were conditioned with total body irradiation (1.25Gy, days -6, -5), thymic irradiation (7Gy, day -1), ATGAM (days -2, -1, 0), anti-CD40L (days 0, 2, 5, 7, 9, 12) and rapamycin for 30 days (day -2 to 28) and tapered down thereafter. MHC-mismatched bone marrow (BM) was infused either on day 0 (Group A) or 2 (Group B) along with the first dose of polyclonal recipient Tregs. Consecutive Treg doses were given during the following week and on day (+/-) 50 for a total of five doses. Tregs were expanded either with artificial antigen presenting cells (aAPC) and donor PBMCs or CD40L-stimulated B cells. Results Animals received cell doses detailed in Figure 1. Among all the Treg-treated animals, 5/6 developed high and long-lasting MC (Figure 2). Among those, the animals that received Tregs stimulated with activated B cells achieved full donor chimerism, which in one was associated with biopsy-proven graft-versus-host-disease (GVHD). The Treg recipient that lost chimerism earlier did so in association with substantial CMV viremia, and associated immune activation. Two of 4 controls lost MC early post-BMT. In one control the MC started to decrease at the time of sacrifice due to infection and the fourth control developed full donor chimerism and GVHD. In vitro, Treg treated animals were donor-hyporesponsive while chimeric.? Discussion Megadose BMT prolonged MC over historical controls that received lower doses of HSC. Prolonged MC was achieved in all the animals that received Tregs except for one with CMV reactivation, and those treated with Tregs generated with activated-B cells had full donor chimerism. In addition, one of the controls achieved full donor chimerism with GVHD. Conclusions Megadose BMT across MHC barriers prolongs donor MC. MC is further prolonged by administering expanded polyclonal recipient Tregs at the time of BMT. NIH R01 OD017949. S10RR027050. S10OD020056.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".