My laboratory has a long-standing interest to understand the development of immune competence, in particular T cell immunity, in recipients of allogeneic hematopoietic cell transplantation (HCT).  Our research bridges the gap between the bench and the clinic with the overall goal of developing novel strategies to accurately diagnose, predict, and therapeutically accelerate post transplant immune reconstitution without increasing graft versus host disease (GvHD).  For many years we have focused on unrelated cord blood transplantation (UCBT) in children as the dominant clinical scenario and laboratory model. Remarkably, despite the HLA-mismatched setting, the antigen inexperienced naïve T cells removed from the immunologically biased fetal-maternal interface will eventually offer protective immunity from viral and opportunistic infections despite ongoing immunosuppression for months after transplant. We were the first to demonstrate the feasibility to in vitro prime cord blood T cells against cytomegalovirus, a significant pathogen. Subsequently, we identified the biological requirements and demonstrated the feasibility to simultaneously expand and induce ex vivo maturation of cord blood T lymphocytes to reach a critical maturational stage in Th1/Tc1 function that can render them receptive to further in vitro priming strategies to generate cytotoxic T lymphocytes (CTL) against human leukemia. Our translational research programs have received support from NCI, NHLBI, and NIAID.

Current work at the University of Pittsburgh:

1. We are testing and developing strategies to overcome barriers of immune ignorance and hypo-responsiveness in patients with acute myeloid leukemia by developing autologous or cord blood donor derived T cell based polyclonal T cell immunotherapy strategies.  
2. Mechanistic studies of immune competence and tolerance in human transplantation. We have ongoing experiments probing:

1. how tolerance will develop in UCBT recipients permitting eventual withdrawal of all immunosuppressive drugs within the first year after transplantation. We are actively probing the role of central deletional mechanism besides peripheral regulatory networks.

2. how immune competence and tolerance will develop following tandem solid organ and T cell-depleted bone marrow transplantations from the same unrelated HLA-mismatched cadaveric donor.  These patients suffer from pulmonary and infectious complications of a variety of primary immune deficiency diseases (PID). In 2009, we were the first to demonstrate the feasibility and success of this strategy in humans when a teenager with Artemis deficient SCID has become immune competent with donor lymphocytes. In vitro hyporeactivity was maintained after Treg depletion and was independent of IL-10 secretion, supporting the notion of clonal deletion as thymocytes of donor origin developed in the multiply HLA-mismatched host thymus. While the University of Pittsburgh is the only center with an active clinical trial to offer hope for PID patients with advanced lung disease, we have designed laboratory experiments to analyze global and mucosal immune competence and to identify the mechanism for recipient-specific hypo-responsiveness in accrued patients. This is a collaborative research program with other members of the Department of Immunology and the Starzl Institute as we probe the acquisition of cadaveric donor-derived  mucosal immunity in heavily infected patients while investigating in parallel the alloreactive milieu at the lung mucosal interface.