Krishna Komanduri, M.D.
Professor of Medicine and Microbiology & Immunology; Director, Sylvester Adult Stem Cell Transplant Program
Description of Research
Dr. Komanduri’s laboratory studies human T cell immune responses to pathogens and allogeneic antigens, with a primary goal of developing better clinical approaches to improve outcomes in the setting of allogeneic stem cell transplantation (SCT) in humans. Research areas include:
To better understand how immune reconstitution occurs after the administration of immunosuppressive chemotherapy and after allogeneic SCT in humans. Since delays in immune recovery are a major cause of death in the clinical SCT setting, development of improved clinical strategies requires a clear understanding of how immune reconstitution occurs after SCT. Dr. Komanduri’s laboratory contributed to one of two simultaneous studies which first demonstrated human thymic function could be measured using molecular approaches to detect recent thymic emigrants in the peripheral human circulation, and that the thymus continues to contribute to T cell homeostasis throughout adulthood. Among the first to apply cytokine flow cytometry to precisely quantitate antigen-specific human T cells in clinical studies, the laboratory has applied this approach to characterize human T cells responses to pathogens, including cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Aspergillus fumigatus, in preclinical and clinical studies.
To better understand the process of graft-versus-host disease (GVHD) in humans, including the cellular populations that mediate GVHD, including T cells and dendritic cells. Dr. Komanduri and his colleagues have developed approaches to characterize the number and function of human alloreactive T cells using flow cytometry, and preclinical approaches that may selectively deplete human donor grafts of alloreactive T cells while preserving antigen-specific human T cells (e.g., specific for pathogens and cancer). They are actively investigating human regulatory T cell (Treg) immunology, including clinical strategies to isolate and expand human Tregs in the clinical setting, aiming to develop graft engineering strategies to decrease GVDH incidence while benefiting immune reconstitution. The group is collaborating with other experts in murine models of GVHD and immune function and those interested in clinical problems related to graft tolerance to develop multidisciplinary approaches to facilitate tolerance after SCT and solid organ/islet transplantation.
To better characterize fine T cell subsets in humans, including early and late memory T cells. Using recently developed methods allowing flow cytometric evaluation of 10+ simultaneous parameters, Dr. Komanduri’s laboratory has optimized approaches to characterize fine subsets of CD4+ and CD8+ T cells defined by the expression of surface markers of maturation (e.g., CCR7, CD27, CD45RA and CD57), cytokine and chemokine production following stimulation (including IFN&gamma, TNF&alpha, IL-2, MIP-1&beta) and activation of intracellular signaling cascades (e.g., the MAPK pathway, as assessed by detection of phospho-ERK). These studies demonstrated early and late memory T cells differ substantially and predictably in expression of surface markers of maturation, and in functional properties defined by cytokine/chemokine production and relative level of phosphoprotein expression following TCR-dependent and independent stimulation. With the laboratory’s demonstration that late memory T cells appear to predominate in the post-SCT setting, and others' findings that adoptive transfer of late-memory T cells appears to confer less protective advantage, it is critical to understand how fine T cell subsets may function in human disease states. This work should facilitate development of more selective strategies of immunosuppression and T cell targeting, critical for advancement in the setting of SCT and solid organ transplantation.
- Performed the first study demonstrating the recovery of cytomegalovirus-specific human T cells following the administration of highly active antiretroviral therapy in HIV-infected individuals. This study was also among the first to demonstrate the clinical utility of cytokine flow cytometry as a measure of antigen-specific T cell responses in humans (Komanduri, et al., Nature Medicine, 1998).
- Participated in a collaborative effort developing the first quantitative approach to measure recent thymic emigrants in human peripheral blood. This was one of two parallel studies that first demonstrated that human thymic function could be measured and that thymopoiesis persists throughout life (Poulin, et al, J Exp Med, 1999).
- Developed novel flow cytometric approaches to characterize human T cell responses to Aspergillus fumigatus (Stanzani, et al., Blood Plenary Paper, 2004) and alloantigens (Martins, et al., Blood Plenary Paper, 2005).
- Demonstrated that immune reconstitution following unrelated donor cord blood transplantation in humans is markedly delayed, and characterized by the failure to recovery thymopoiesis, relative to other allogeneic stem cell transplant recipients (Komanduri, et al., Blood, 2007).
Selected Cancer-Related Publications
- Saliba RM, Komanduri KV, Giralt S, de Souza J, Patah P, Oran B, Couriel D, Rondon G, Champlin RE, de Lima M. Leukemia burden delays lymphocyte and platelet recovery after allo-SCT for AML. Bone Marrow Transplant 43:685-92, 2009. Read more »
Leader of the Multidisciplinary Research Program: Tumor Immunobiology Program