Superior immune reconstitution using Treg-expanded donor cells versus PTCy treatment in preclinical HSCT models
Dietlinde Wolf, Cameron S. Bader, Henry Barreras, Sabrina Copsel, Brent J. Pfeiffer, Casey O. Lightbourn, Norman H. Altman, Krishna V. Komanduri, Robert B. Levy
Dietlinde Wolf, Cameron S. Bader, Henry Barreras, Sabrina Copsel, Brent J. Pfeiffer, Casey O. Lightbourn, Norman H. Altman, Krishna V. Komanduri, Robert B. Levy
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Research Article Immunology Transplantation

Superior immune reconstitution using Treg-expanded donor cells versus PTCy treatment in preclinical HSCT models

Abstract

Posttransplant cyclophosphamide (PTCy) has been found to be effective in ameliorating acute graft-versus-host disease (GVHD) in patients following allogeneic hematopoietic stem cell transplantation (aHSCT). Adoptive transfer of high numbers of donor Tregs in experimental aHSCT has shown promise as a therapeutic modality for GVHD regulation. We recently described a strategy for in vivo Treg expansion targeting two receptors: TNFRSF25 and CD25. To date, there have been no direct comparisons between the use of PTCy and Tregs regarding outcome and immune reconstitution within identical groups of transplanted mice. Here, we assessed these two strategies and found both decreased clinical GVHD and improved survival long term. However, recipients transplanted with Treg-expanded donor cells (TrED) exhibited less weight loss early after HSCT. Additionally, TrED recipients demonstrated less thymic damage, significantly more recent thymic emigrants, and more rapid lymphoid engraftment. Three months after HSCT, PTCy-treated and TrED recipients showed tolerance to F1 skin allografts and comparable immune function. Overall, TrED was found superior to PTCy with regard to weight loss early after transplant and initial lymphoid engraftment. Based on these findings, we speculate that morbidity and mortality after transplant could be diminished following TrED transplant into aHSCT recipients, and, therefore, that TrED could provide a promising clinical strategy for GVHD prophylaxis.

Authors

Dietlinde Wolf, Cameron S. Bader, Henry Barreras, Sabrina Copsel, Brent J. Pfeiffer, Casey O. Lightbourn, Norman H. Altman, Krishna V. Komanduri, Robert B. Levy

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Figure 6

Faster thymic recovery in TrED recipients compared with PTCy-treated animals and GVHD controls early after HSCT.

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Faster thymic recovery in TrED recipients compared with PTCy-treated ani...
Three weeks after HSCT, thymic tissue was analyzed for total cell numbers (A), phenotype (B), engraftment (C), and Tregs (D) (n = 4–6). (A) Significantly greater cell numbers were identified in TrED recipients compared with PTCy-treated and control animals. Data from 3 pooled independent experiments are shown as mean ± SEM; ANOVA with Bonferroni correction was applied for multiple comparisons. (B) Normal levels of CD4+CD8– and CD4–CD8+ SP as well as DP thymocytes are detected in TrED recipients. PTC-treated animals and GVHD controls show an abnormal pattern of thymocytes, with few DP cells and a prevalence of SP cells (left). Representative dot plots for each group are shown (right). (C) Assessment of the origin of developing thymocytes shows a significantly faster engraftment from donor CD45.1+ stem cells in the CD4+ and CD8+ SP compartment in TrED recipients compared with PTCy-treated animals and GVHD controls. Data are expressed as mean ± SEM and were analyzed by a 2-tailed unpaired t test. Data are pooled from 2 independent experiments. (D) TrED recipients exhibit higher frequencies and numbers of donor CD4+Foxp3+ Tregs. Data from 3 pooled independent experiments are shown as mean ± SEM; ANOVA with Bonferroni correction was applied for multiple comparisons. **P < 0.01; ***P < 0.001; ****P < 0.0001.