Immune deficiency causes significant morbidity and mortality in hematopoietic cell transplant (HCT) recipients. The clinical significance is especially evident when utilizing high doses of cytotoxic conditioning, donor HSC sources that are HLA-mismatched or contain low numbers of mature T lymphocytes, as would be the case with umbilical cord blood (UCB) transplants. We have observed a high incidence of severe or fatal intracellular and DNA viral (CMV;EBV;HHV6;adenovirus) infections in UCB transplant recipients. A major cause is loss of thymopoietic capacity, and impaired T cell recovery as a result of age, chemoradiotherapy or graft-versus-host-disease. Thymopoiesis depends on the interaction of the thymic stroma-derived receptors and ligands. Damage to thymic epithelial cells (TECs) by pre-transplant conditioning impairs the generation of mature T cells following transplant and predisposes the recipient to infections. Our central hypothesis is that thymic microenvironmental injury is the major limiting factor for slow T cell reconstitution and function in UCB transplant recipients, indicated by the predisposition for late infections. TEC differentiation, proliferation, and survival are controlled by both cell intrinsic and extrinsic factors. Thymocyte precursors and TECs engage in "cross-talk" such that bidirectional signaling mechanisms provided by and to both thymocytes and TECs are essential for their mutual proliferation and survival. Our preliminary data in mice indicate that there is a direct correlation between the number of mature thymocytes and TECs, especially those located in the thymic medulla, which serves as the primary site of negative selection and thymic egress into the periphery. With the operational hypothesis that the rapidity of recovery of effective thymopoiesis is limited both by ineffective :TEC cross-talk (aim 1) and the relative paucity of endogenous TECs that escape conditioning regimens (aims 1, 2). We will pursue two approaches (specific aims) to overcome the quantitative and qualitative defect in TEC support of thymopoiesis.
Aim 1. To determine whether TEC regeneration and thymopoietic recovery is limited by inadequate cross-talk between thymocyte precursors and TECs post-HSCT.
Aim 2. To devise and test novel TEC replacement strategies based upon TEC developmental cues and using inducible pluripotent stem cell technology.
Our goal is to develop clinically relevant approaches to prevent the profound T cell immune deficiency that occurs post-transplant in young and especially aged recipients of UCB grafts. This is a major source of morbidity and mortality post-transplant limiting the more widespread use of this methodology for the treatment of malignant and non-malignant disorders.
|Foley, Bree; Felices, Martin; Cichocki, Frank et al. (2014) The biology of NK cells and their receptors affects clinical outcomes after hematopoietic cell transplantation (HCT). Immunol Rev 258:45-63|
|Mitchell, Richard; Wagner, John E; Hirsch, Betsy et al. (2014) Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia. Br J Haematol 164:384-95|
|Miller, Jeffrey S; Rooney, Cliona M; Curtsinger, Julie et al. (2014) Expansion and homing of adoptively transferred human natural killer cells in immunodeficient mice varies with product preparation and in vivo cytokine administration: implications for clinical therapy. Biol Blood Marrow Transplant 20:1252-7|
|Felices, Martin; Lenvik, Todd R; Ankarlo, Dave E M et al. (2014) Functional NK cell repertoires are maintained through IL-2R? and Fas ligand. J Immunol 192:3889-97|
|Gleason, Michelle K; Ross, Julie A; Warlick, Erica D et al. (2014) CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 123:3016-26|
|Kharbanda, Sandhya; Smith, Angela R; Hutchinson, Stephanie K et al. (2014) Unrelated donor allogeneic hematopoietic stem cell transplantation for patients with hemoglobinopathies using a reduced-intensity conditioning regimen and third-party mesenchymal stromal cells. Biol Blood Marrow Transplant 20:581-6|
|Sawitzki, Birgit; Brunstein, Claudio; Meisel, Christian et al. (2014) Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood Toll-like receptor 5 mRNA expression. Biol Blood Marrow Transplant 20:173-82|
|Ustun, Celalettin; Bachanova, Veronika; Shanley, Ryan et al. (2014) Importance of donor ethnicity/race matching in unrelated adult and cord blood allogeneic hematopoietic cell transplant. Leuk Lymphoma 55:358-64|
|Kaliyaperumal, Saravanan; Watkins, Benjamin; Sharma, Prachi et al. (2014) CD8-predominant T-cell CNS infiltration accompanies GVHD in primates and is improved with immunoprophylaxis. Blood 123:1967-9|
|Rogosheske, J R; Fargen, A D; DeFor, T E et al. (2014) Higher therapeutic CsA levels early post transplantation reduce risk of acute GVHD and improves survival. Bone Marrow Transplant 49:122-5|
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