Umbilical cord blood is increasingly utilized as a stem cell source for allogeneic stem cell transplant candidates lacking suitable matched-sibling donors. Advantages offered by the use of umbilical cord blood grafts over other sources include the possibility of non-invasive procurement, more rapid availability without the need for the more prolonged process of screening and obtaining stem cells from an unrelated donor and the apparently greater tolerance for incompletely HLA-matched products. These advantages are paramount for recipients in underrepresented minority groups, for whom the prospect of locating a MUD registry donor remains relatively diminished. Unfortunately, infection is the major cause of early mortality after CBT, and occurs primarily due to delayed T cell immune reconstitution. To develop approaches to actively intervene to improve T cell recovery, it is crucial to systematically study the correlates of T cell immune recovery in the context of novel clinical CBT trials. We hypothesize that the recipient thymus contributes to the recovery of functional antigen-specific T cell responses after CBT, and that variability in the ability to recovery thymopoiesis after CBT will predict the likelihood of functional T cell recovery. Additionally, we predict that host and/or clinical factors, including age and conditioning regimen, will be important factors in governing the recovery of thymopoiesis. We further hypothesize that thymopoiesis may be necessary to facilitate the recovery of regulatory T cells (Tregs) and that robust Treg recovery is protective for the development of chronic GVHD. Finally, we hypothesize that graft manipulation strategies, including ex vivo expansion and the infusion of multiple units, will influence both thymopoetic recovery and the recovery of peripheral T cells, including antigen-specific memory cells and Tregs. We will test these hypotheses in the following specific Aims: 1. To examine the importance of host factors and conditioning regimen on the recovery of a diverse and functional T cell repertoire after CBT in children and adults. 2. To determine how regulatory T cell recovery is influenced by thymopoiesis and whether regulatory T cells influence the occurrence of chronic GVHD in CBT recipients. 3. To define how donor graft manipulations that increase infused CBT stem cell numbers influence the recovery of thymopoiesis and T cell immune recovery. For many patients with high-risk or relapsed hematological malignancies, and other diseases of children including inherited metabolic disorders, allogeneic stem cell transplantation (SCT) is the only curative treatment option. For individuals lacking a suitable immunologically matched family or registry donor, umbilical cord blood (CB) represents an important source of stem cells that can be used to regenerate normal blood cell production in transplant recipients. Unfortunately, the leading cause of mortality after CB transplantation is infection caused by poor T cell recovery. In this proposal, we will perform ancillary studies that will dissect the determinants and correlates of protective immune recovery in the setting of novel clinical approaches being applied to improve CB transplant outcomes. The impact of both donor graft and host factors will be studied, to help define subpopulations at greatest risk for mortality, and to design safer and more curative approaches for the future.

Public Health Relevance

For many patients with high-risk or relapsed hematological malignancies, and other diseases of children including inherited metabolic disorders, allogeneic stem cell transplantation (SCT) is the only curative treatment option. For individuals lacking a suitable immunologically matched family or registry donor, umbilical cord blood (CB) represents an important source of stem cells that can be used to regenerate normal blood cell production in transplant recipients. Unfortunately, the leading cause of mortality after CB transplantation is infection caused by poor T cell recovery. In this proposal, we will perform ancillary studies that will dissect the determinants and correlates of protective immune recovery in the setting of novel clinical approaches being applied to improve CB transplant outcomes. The impact of both donor graft and host factors will be studied, to help define subpopulations at greatest risk for mortality, and to design safer and more curative approaches for the future.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL091749-02
Application #
7565984
Study Section
Special Emphasis Panel (ZHL1-CSR-H (O1))
Program Officer
Wagner, Elizabeth
Project Start
2008-02-11
Project End
2011-12-31
Budget Start
2009-04-01
Budget End
2009-12-31
Support Year
2
Fiscal Year
2009
Total Cost
$413,250
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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