Anti-GVHD Effect of Antithymocyte Globulin is Mediated by Antibodies Binding to T Cells and Regulatory NK Cells, and Less So or Not at All by Antibodies Binding to Other Mononuclear Cell Subsets
Bibliographic record
Abstract
Introduction: Polyclonal rabbit-anti-human T cell globulin (ATG) may decrease the likelihood of graft-vs-host disease (GVHD) without increasing the likelihood of relapse.ATG is polyclonal and the anti-GVHD effect may be mediated through killing/inhibition of one or several lymphocyte subsets (eg, T cells) or their subsets (eg, na€ ıve T cells).To understand the mechanism of action of ATG on GVHD, we determined levels of which ATG fraction (capable of binding to which cell subset) are associated with subsequent development of GVHD.Patients & Methods: We studied 121 patients whose myeloablative conditioning included 4.5 mg/kg ATG (Thymoglobulin).Using flow cytometry, levels of the following ATG fractions in serum from day 7 were determined: capable of binding to naive or memory B cells; naive, central memory (CM) or effector memory (EM) CD4 and CD8 T cells, EM CD8 T cells not expressing CD45RA (EMRA-); cytolytic, regulatory or CD16 + CD56 -NK cells; monocytes and dendritic cells (DCs).ATG levels in patients with vs without aGVHD or cGVHD were compared using Mann-Whitney test.For each fraction where levels were significantly different (p\0.05),we determined if patients with high fraction level had a significantly lower likelihood of aGVHD or cGVHD using log-binomial regression models.Results: In univariate analyses, significantly lower levels of ATG fractions on the following subsets were found in patients developing aGVHD: binding to naive CD4 and CD8 T cells, EM CD4 T cells, and regulatory NK cells, or cGvHD: binding to naive CD4 and CD8 T cells, CM and EM CD4 T cells, and regulatory NK cells.In multivariate analyses, high levels of the following ATG fractions were associated with a low likelihood of aGVHD: binding to naive CD4 T cells (RR 5 .33,p 5 .001),EM CD4 T cells (RR 5 .30,p \ .001),naive CD8 T cells (RR 5 .33,p 5 .002)and regulatory NK cells (RR 5 .36,p 5 .001)or low likelihood of cGVHD: binding to naive CD4 T cells (RR 5 .59,p 5 .028),CM CD4 T cells (RR 5 .49,p 5 .009),EM CD4 T cells (RR 5 .51,p 5 .006),naive CD8 T cells (RR 5 .46,p 5 .005)and regulatory NK cells (RR 5 .55,p 5 .036).Conclusion: For both aGVHD and cGVHD, the anti-GVHD effect with relapse-neutral effect of ATG appears to be mediated by antibodies to antigens expressed on naive T cells (both CD4 and CD8), EM CD4 T cells and regulatory NK cells.This is the first step towards identifying the antibody(ies) within ATG important for the anti-GVHD effect without impacting relapse.
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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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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".