Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age

Castermans, Emilie; Hannon, Muriel; Dutrieux, Jacques; Humblet-Baron, Stéphanie; Seidel, Laurence; Cheynier, Rémi; Willems, Évelyne; Gothot, André; Vanbellinghen, Jean-François; Geenen, Vincent; Sandmaier, Brenda M.; Storb, Rainer; Béguin, Yves; Baron, Frédéric

doi:10.3324/haematol.2010.029702

Cited by 74 publications

(73 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our studies enrich previous clinical studies using nonmyeloablative conditioning for allogeneic haematopoietic cell transplantation investigating the recovery of total CD20, CD4 and CD8 cell populations as well as the rates of naive CD4 T cell recovery in older versus younger patients [88]. This group used long-term immunosuppression that resembled the regimens used in our study in many of these patients because of chronic graft-versus-host disease (GVHD), but were not able to evaluate the pre-versus post-treatment in memory/naive profiles.…”

Section: Discussionsupporting

confidence: 63%

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

Meyer

Walker

Dewane

et al. 2015

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryIn this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease.

show abstract

Section: Discussionsupporting

confidence: 63%

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

Meyer

Walker

Dewane

et al. 2015

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…Regeneration of a broad and functionally competent TCR repertoire after allogeneic HSCT requires intact thymic function, which is, however, compromised by pre-transplant conditioning, by an age-related involution of the thymus, and by the donor-derived allo-reactive immune response to recipient tissues. [5][6][7][8][9][10]12,13,21,22 Apart from age, most pre-transplant variables did not affect post-transplant thymic function in our study. Age was also the only pre-transplant variable consistently associated with impaired post-transplantation thymopoiesis in previous studies.…”

Section: Discussionmentioning

confidence: 56%

“…Age was also the only pre-transplant variable consistently associated with impaired post-transplantation thymopoiesis in previous studies. [5][6][7][8][9][10]12,13,21 Retrospectively, we did not find an association between acute GvHD and impaired thymopoiesis, but more patients in whom thymopoiesis failed to recover at 12 months had a history of extensive chronic GVHD, which had occurred during the first year post-transplant. Several clinical and experimental studies have highlighted that GvHD severely impairs thymopoiesis, although recapitulation of thymic function after a history of acute GvHD is still possible.…”

Section: Discussionmentioning

confidence: 79%

“…Hazard ratios referring to the risk of subsequent infections were very high in the present study, which may be explained by the predominant role of thymic function in our study population of T-cell recovery. Recipients of T-cell-replete grafts, as well as recipients of non-myeloablative grafts 21 may benefit from the immune effector cells infused with the graft and depend less stringently on thymopoiesis. In addition, given the adverse effect of high-dose radiotherapy 22,23 on thymic epithelium, both the myeloablative conditioning regimen and T-cell-depletion strategy may have acted in concert by impairing thymopoiesis without providing compensation by peripheral donor T-cell recovery.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

Wils¹,

Holt²,

Broers³

et al. 2011

Haematologica

View full text Add to dashboard Cite

BackgroundRecovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation is considered pivotal for full immune competence. However, it is still unclear to what extent insufficient recovery of thymopoiesis predicts for subsequent opportunistic infections and non-relapse mortality. Design and MethodsA detailed survey of all post-engraftment infectious complications, non-relapse mortality and overall survival during long-term follow-up was performed in 83 recipients of allogeneic stem cell grafts after myeloablative conditioning. Recovery of thymopoiesis was assessed using analysis of signal joint T-cell receptor rearrangement excision circles. The impact of recovery of thymopoiesis at 2, 6, 9 and 12 months post-transplantation on clinical outcome beyond those time points was evaluated by univariate and multivariate Cox regression analyses. ResultsThe cumulative incidence of severe infections at 12 months after transplantation was 66% with a median number of 1.64 severe infectious episodes per patient. Patients in whom thymopoiesis did not recover were at significantly higher risk of severe infections according to multivariable analysis. Hazard ratios indicated 3-and 9-fold increases in severe infections at 6 and 12 months, respectively. Impaired recovery of thymopoiesis also translated into a higher risk of non-relapse mortality and outweighed pre-transplant risk factors including age, donor type, and disease risk-status. ConclusionsThese results indicate that patients who fail to recover thymopoiesis after allogeneic hematopoietic stem cell transplantation are at very high risk of severe infections and adverse clinical outcome.Key words: thymopoiesis, opportunistic infections, transplantation outcome, TREC. Haematologica 2011;96(12):1846-1854. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Wils E-J, van der Holt B, Broers AEC, Posthumus-van Sluijs SJ, Gratama J-W, Braakman E and Cornelissen JJ. Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients. Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

show abstract

“…For patients where T-cell differentiation and/or function is affected, successful transplantation also necessitates that HSC or their progeny home to the thymus, the major site of T-cell differentiation. While the thymus was previously thought to be active only during infancy and childhood, we now know that the thymus continues to generate new T cells during adulthood; patients undergoing stem cell transplantation between 30 and 40 years of age have a high probability of thymic rebound while late thymic recovery has been detected in patients up to 50 years of age [1,2].…”

Section: Introductionmentioning

confidence: 99%

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

2013

View full text Add to dashboard Cite

Allogeneic hematopoietic stem cell (HSC) transplantation can cure patients suffering from diverse genetic and acquired diseases as well as cancers. Nevertheless, under conditions where T-cell reconstitution is critical, the entry of donor progenitors into the thymus remains a major bottleneck. It is assumed that following the intravenous injection of HSC, they first home to the BM. More committed progenitors can then be exported to the thymus in response to a myriad of signals regulating thymus seeding. Notably although, the thymus is not continually receptive to the import of hematopoietic progenitors. Furthermore, as stem cells with self-renewing capacity do not take up residence in the thymus under physiological conditions, the periodic colonization of the thymus is essential for the sustained differentiation of T lymphocytes. As such, we and others have invested significant efforts into exploring avenues that might foster a long-term thymus-autonomous differentiation. Here, we review strategic approaches that have resulted in long-term T-cell differentiation in immunodeficient (SCID) mice, even across histocompatibility barriers. These include the forced thymic entry of BM precursors by their direct intrathymic injection as well as the transplantation of neonatal thymi. The capacity of the thymus to support hematopoietic progenitors with renewal potential will hopefully promote the development of new therapeutic strategies aimed at enhancing T-cell differentiation in patients undergoing HSC transplantation.

show abstract

Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age

Cited by 74 publications

References 62 publications

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

Contact Info

Product

Resources

About