Differences In the Short Term Granulocyte and Platelet Producing Activity of Cord Blood and Mobilized Peripheral Blood Transplants Revealed by Quantitative Repopulation Assays In NOD/SCID-IL-2Rγc−/− Mice.
Notice bibliographique
Résumé
Abstract Abstract 3733 Human G-CSF-mobilized peripheral blood (mPB) progenitor harvests collected by leukapheresis have become the usual transplant of choice when a suitable normal histocompatible or unrelated adult donor is available for patients requiring a transplant. Unfortunately, for most such patients such a donor is not available and, for these individuals, an autotransplant or unrelated cord blood (CB) unit provide potential alternatives. Autologous harvests are frequently compromised by prior exposure to chemotherapy, and the relatively small size of a single CB unit, can also pose significant problems, particularly in adult recipients. These typically involve pronounced delays in neutrophil recovery and almost always a protracted and/or poor recovery in platelet output. Interestingly, although the simultaneous transplantation of multiple CB units has successfully reduced graft failure, timely hematopoietic recovery is still not commonly achieved, especially for the platelets. There is thus a compelling need to understand the types of repopulating cells that are present in different mPB and CB harvests and how these may vary numerically and biologically. Such information is key to devising better surrogate predictors of adequate engrafting potential and as a first step towards developing new approaches to improve the utility of CB and poor mPB harvests for clinical transplant applications. To pursue these issues, we have developed new assays for quantifying different types of human cells with different durabilities of platelet and granulocyte generating activity in sublethally irradiated NOD/SCID-IL-2Rγc−/− (NSG) mice and have now used these assays to compare the numbers and output properties of different phenotypically characterized subpopulations of cells present in CB and normal mPB samples. Consistent with previous reports, we found that >90% of the week-3 bone marrow repopulating activity in transplanted mice was contained within the Lin−ALDH+ fraction regardless of the source of the human cells tested. However, a substantial proportion of early (week 2) platelet repopulating activity came from the Lin−ALDH− fraction of both CB and mPB (30% for CB and 61% for mPB, decreasing to 12% and 16% respectively by week 3). In vitro CFU-Mk (and CFU-GM/BFU-E/CFU-GEMM) assays reflected a similar differential distribution between the Lin−ALDH+ and Lin−ALDH− cells from the two sources, suggesting possible overlap in the corresponding in vitro and in vivo endpoints. Interestingly, at 3 weeks post-transplant, we found the Lin−ALDH+ cells from mPB produced more of the GM cells than the platelets as compared to the Lin−ALDH+ cells from CB. Limiting dilution assays revealed that the actual frequency of week-3 GM-repopulating cells (GMRC-3wks) and platelet-repopulating cells (PRC-3wks) in Lin−ALDH+ cells in mPB (1/2500, 95% CI=1/1500–1/4200 and 1/3300, 95% CI=1/1900–1/5600) is actually about 3-fold lower (p<0.05) than that in CB (1/780, 95% CI=1/470–1/1300 and 1/1300, 95% CI=1/800–1/2000). Thus, the average mature cell output per RC of either type is correspondingly higher in mPB than in CB (≂f8-fold for GMRC-3wks and 4-fold for PRC-3wks). Based on these findings and knowledge of the median cell dose used for clinical transplants of mPB and a single CB unit, we estimated that adults transplanted with the latter would receive ≂f35-fold less GMRC-3wks and PRC-3wks than what would be given in a typical mPB transplant. In summary, our results show that discontinued ALDH activity identifies many of the cells in both mPB and CB that are responsible for very rapid (within 2–3 weeks) but transient production of mature myeloid cells and platelets post-transplant versus those with persistent ALDH activity that are required for the more prolonged output of these cells (>3 weeks). In addition, our results demonstrate that the 3-week RCs in mPB and CB differ in their average clonal outputs of mature GM cells and platelets in vivo, suggesting ontogeny-related changes in the mechanisms that determine this functional parameter. Disclosures: No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».