Graft T cells in hematopoietic stem cell transplant

Although the major complications of transplant (such as graft-versus-host disease, graft rejection, viral infections) are related to T cells, the graft size is determined by a surrogate marker for stem cells (CD34+) and not by T-cells. The graft T-cell content is rarely measured.
Published in Immunology

The stem cells and immune cells play pivotal roles in hematopoietic cell grafting. Donor hematopoietic stem cells are self-replicating, engraft in the bone marrow niche, differentiate into multiple types of blood cells, and thus maintain long-term hematopoiesis. The immune cells specifically long-lived donor T cells born out of donor thymus i.e. graft T cells also engraft in the immune niche and facilitate early immune-reconstitution through process called homeostatic proliferation. The later and long-term immune-reconstitution originates from the genesis of new T cells from the recipient’s thymus, a process called thymopoiesis, which typically begins 3 to 6 months after the transplant. These new T cells egressed from the recipient’s thymus mediate tolerance and hence allow withdrawal of immunosuppression after hematopoietic stem cell transplantation.

The early immune-reconstitution through the process of homeostatic proliferation protects from viral infections but can also increase the risk of graft-versus-host disease. Despite the crucial roles of graft T cells in graft-versus-host-disease and protection from viral infections, T-cell content in the graft is rarely measured. The graft size is determined by CD34+ marker (a surrogate marker for stem cells) and not by T-cell content in the graft.

The graft T cells are naïve, memory and effectors cells. Alemtuzumab, a CD52 antibody is a robust T-cell depleting serotherapy that preferentially depletes naïve T cells over memory-effector T cells. Thus, alemtuzumab relatively spares antigen-specific memory effector T cells over antigen-inexperienced naïve T cells. The historical technique of determining graft size based on CD34+ cells with alemtuzumab serotherapy is typically capped for CD34+ cells of 5 million/kg of recipient weight and consists of 200-300 million/kg T cells. This technique of grafting results in delayed immune-reconstitution, increased risk of viral infections and graft rejection. We therefore hypothesised that higher dose of T cells in patients receiving alemtuzumab serotherapy would spare memory-effector T cells and thus facilitate early antigen-specific immune-reconstitution, reduce the risk of viral infection without increasing the risk of graft-versus-host disease.

To improve the T-cell immune-reconstitution, we determined the graft size by capping for T cells at 600 million/kg of recipient weight. The capping for T cells allowed grafting with high numbers of CD34+ and T cells. We found correlation between the graft T-cell content and CD4+ T-cell reconstitution. The early reconstituting T cells had memory-effector phenotype and there was conspicuous absence of naïve T cells. This new method of capping for T-cell content in the graft with alemtuzumab serotherapy led to early immune reconstitution.

CMV viremia was seen in 50% of patients. However, the course of CMV viremia was predictable, and resolution of CMV viremia was associated with CD4+ and CD8+ T-cell responses. Thus, it is likely that the early reconstituting alemtuzumab-spared memory-effector T cells possibly also mediated an anti-CMV effect.

Although, there was a statistically significant correlation between acute graft-versus-host disease and T-cell dose, the incidence of severe acute graft-versus-host disease was low. Mixed chimerism was observed in 1/3rd patients but there was no loss of graft. And more importantly, the disease-free survival in this cohort of patients was excellent and no patient had graft failure or chronic graft versus host disease.  

This is the first study to demonstrate early immune-reconstitution in patients receiving alemtuzumab serotherapy. The study is also the first to explore the role of graft T-cell content in post-transplant immune-reconstitution. Although the study is retrospective, the determination of graft size based on T-cell content rather than CD34+ content has the potential to improve outcomes in patients receiving alemtuzumab serotherapy for non-malignant disorders.

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Bone Marrow Transplantation
Life Sciences > Biological Sciences > Immunology > Transplant immunology > Bone Marrow Transplantation
Transplant immunology
Life Sciences > Biological Sciences > Immunology > Transplant immunology
Life Sciences > Biological Sciences > Immunology > Transplant immunology > Allotransplantation

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