Hematopoietic stem cell transplantation (HSCT) is a curative option for the treatment of numerous malignancies and inherited genetic disorders; however, the success of the procedure is hampered by numerous complications. Pulmonary complications cause significant morbidity and mortality following HSCT and most notably include infections, idiopathic pneumonia syndrome (IPS), bronchiolitis obliterans (BOS) and cryptogenic organizing pneumonia (COP). These conditions are characterized by acute and chronic inflammation and can include tissue fibrosis, severely damaging lung function. While more common following allogeneic HSCT, IPS, BOS and COP have also been reported as a complication of autologous HSCT and their diagnosis is defined, in part, by the absence of infection. However, accumulating evidence suggests these lung pathologies could represent immunopathology that develops as a consequence of a previous viral infection, or possibly due to an occult infection. Importantly, herpesviruses were recently identified as the most common occult infection in patients with IPS. We have developed a murine model in which syngeneic bone marrow transplant (BMT) mice that are fully reconstituted with donor-derived cells develop severe lung pathology characterized by interstitial pneumonitis, vasculitis and fibrosis following infection with murine gamma herpesvirus-68 (?HV-68). This lung pathology is well established at 21 days post-infection when lytic viral infection has been cleared and the virus has established latency. Our published and preliminary findings suggest the process of BMT alters the phenotype of lung dendritic cells (DCs). DCs from BMT mice overproduce IL-1?, IL-6, TGF? and IL-23. These BMT-induced DC alterations lead to the skewing of the CD4 response to a Th17, rather than a Th1 response post-infection with ?HV-68. The consequence of this persistent skewing is the development of IL-17-dependent pneumonitis and fibrosis. In addition, we have evidence that adoptive transfer of DCs from infected control mice into BMT mice can restore Th1 cell priming and limit development of lung immunopathology focusing our current studies on trying to understand how the process of BMT impairs the function of lung DCs. Preliminary data suggest that lung DCs in BMT mice are characterized by reduced autophagy and impaired expression of the Notch ligand, delta like ligand 4 (DLL4). Reduced autophagy could explain the overproduction of IL-1? if DCs in BMT mice are unable to clear activated inflammasomes. Notch signaling is highly context-dependent and can both enhance and inhibit T cell signaling. Thus, the overall goal of the proposed research is to mechanistically understand how DCs are altered following HSCT in ways that promote pathologic rather than protective immune responses to respiratory viruses. Most importantly, we will determine whether these molecular alterations that characterize murine DCs post-BMT are also evident in DCs from human patients experiencing lung dysfunction post-HSCT. Our hypothesis is that HSCT results in reduced autophagy and impaired DLL4 expression in lung DCs in response to ?HV-68 infection, and that this alteration in DCs promotes pathologic Th17 rather than protective Th1 responses. We will address this hypothesis in the following specific aims.
Aim 1) To identify the relevant DC population responsible for priming ?HV-68-specific T cell responses and determine whether autophagy is impaired in these DCs post-BMT and ?HV-68 infection Aim 2) To determine if BMT DCs are characterized by defective Notch ligand expression or altered costimulatory receptors Aim 3) To determine the translational relevance of these findings by determining whether the responses are specific to ?-herpesviruses, and whether similar DC phenotypes are noted in patients post-HSCT Completion of these specific aims will be significant for several reasons. This work will solidify the critical role that latent or occult infection play in causing ?idiopathic? lung pathology post-HSCT and will provide novel information regarding the mechanistic alterations that occur in DCs post-transplant. Most importantly, this work will identify and test strategies to restore DC function post-BMT and will provide translational proof that these phenotypes characterize human DCs post-HSCT.

Public Health Relevance

Statement: Hematopoietic stem cell transplantation as a cure for genetic and malignant diseases is hampered by the high incidence of pulmonary complications including development of fibrotic lung remodeling. Currently, these complications are not believed to be caused by infection, but our work suggests that herpesvirus infection can cause this type of lung pathology, even when the virus is no longer replicating. This pathology develops as a result of an inappropriate IL-17 response caused by altered lung dendritic cells in response to the viral infection. This work will explore the molecular alterations that occur in dendritic cells post-transplant that make the host susceptible to this pathologic remodeling, and will explore ways to restore lung homeostasis. This work could significantly enhance the efficacy and safety of stem cell transplant therapy for many patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Craig, Matt
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
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