Research Overview
Inhibition of aberrant alloantigen presentation in the GI tract
While the pathways that mediate GVHD are well established (i.e. donor T cells and cytokines), those that initiate the process remain poorly defined. We have led the field in understanding the role of various antigen presenting cell subsets in this process and have identified novel antigen presenting cell subsets in the GI tract as critical to GVHD lethality. We are now in the late phases of our preclinical work and are planning translational studies to the clinic. The aim is to prevent gut GVHD in patients undergoing BMT.
Preventing cytokine dysregulation and pathogenic T cell differentiation after BMT
Donor T cells are required to induce both acute and chronic GVHD, but the manifestations of these diseases are quite different. Acute GVHD induces target tissue apoptosis, chronic GVHD results in fibrosis. Moreover, the former affects the GI tract at high frequency, the latter skin, lung, eyes and mouth. We have shown the critical importance of IL-6 in acute GVHD and Th17/Th22 differentiation in chronic GVHD. Critically, we have shown how this T cell differentiation paradigm results in donor macrophage-dependent fibrosis. We continue to undertake preclinical studies to understand the antigenic determinants of various T cell differentiation programs and have been involved in the development of a number of new drugs for chronic GVHD that specifically target these aberrant immune pathways. We continue in this endeavor and now undertake both preclinical studies and immune analysis of clinical studies in both acute and chronic GVHD.
Improving regulatory T cell function during transplantation
Regulatory T cells are critical for the establishment of tolerance after BMT and GVHD is characterized by dramatic quantitative and qualitative defects in the FoxP3+ regulatory T cell population. Indeed, we and others have demonstrated that chronic GVHD can be reversed by correction of this defect. Most recently we have identified the importance of IL-10 producing type 1 regulatory T (Tr1) cells in disease and we continue to undertake preclinical work to optimize therapeutic strategies to improve regulatory T cell homeostasis after BMT.
These approaches include the transduction of T cells with the transcription factor Eomes to induce Tr1 differentiation in the BMT setting.
Understanding the immunological control of CMV reactivation
Opportunistic infection remains a major complication after BMT and CMV represents the prototypic pathogen. The mechanisms controlling the reactivation of CMV from a latent state in immunocompromised patients has been thought to center around cell mediated immunity. However, due to the absence of preclinical models, this has not been formally tested in a rigorous cause and effect fashion. We have developed the first preclinical models of murine CMV reactivation after BMT and have defined a number of hitherto unexpected pathways of immune control, both cellular and humoral. Informed by these new systems, we are analyzing these paradigms in clinical samples with a view to the development of new therapeutic paradigms.
Promoting GVL effects after allogenic BMT
Relapse of underlying malignancy is now the major cause of treatment failure after BMT and approaches to improve immune-mediated graft-versus leukemia (GVL) effects are urgently needed in patients who are identified as at high-risk or have already relapsed after BMT. We have generated a number of novel models of primary acute myeloid and acute lymphoblastic leukemia that enable the optimization of approaches to maximize GVL, whilst ensuring that such strategies do not result in unacceptable GVHD. These approaches to date revolve around the improvement of leukemia specific Tc1 differentiation and inhibition of pathogenic Tc17 differentiation that induces GVHD but not GVL. A number of therapeutic approaches based around these principles are in various stages of testing in the clinic and continue to evolve, informed by new preclinical and clinical data.
Refining immune-mediated control of myeloma after autologous SCT
Autologous stem cell transplantation (ASCT) is a standard of care in the treatment of multiple myeloma, prolonging disease control and survival. ASCT has been thought to be a mechanism of delivering dose intensive chemotherapy and subsequent cytoreduction. However, ASCT also induces profound inflammation and lymphodepletion and we have recently developed new models of myeloma that demonstrate that this therapy results in immune control on myeloma. Indeed, we have shown that the progression of myeloma after ASCT is a result of immune escape that can be prevented by a number of new immunotherapies when utilized in the immediate post-transplant period. We are continuing our studies to optimize novel immunotherapy approaches after ASCT in both preclinical and planned clinical trials.
Defining T cell exhaustion in the marrow
We have also used these preclinical models to uncover novel T cell phenotypes and hematological malignancies and found that CD8 T cells with a terminally exhausted phenotype could retain functional capacity in the bone marrow. Click this link for open access to our recent publication (April 2024) in Science Immunology.
© 2025 Fred Hutchinson Cancer Center, a 501(c)(3) nonprofit organization.