CD8-predominant T-cell CNS infiltration accompanies GVHD in primates and is improved with immunoprophylaxis

Kaliyaperumal, Saravanan; Watkins, Benjamin; Sharma, Prachi; Furlan, Scott N.; Ramakrishnan, Swetha; Giver, Cynthia R.; García, Anapatricia; Courtney, Cynthia L.; Knight, Heather; Strobert, Elizabeth; Elder, Eric; Crenshaw, Timothy; Blazar, Bruce R.; Waller, Edmund K.; Westmoreland, Susan; Kean, Leslie S.

doi:10.1182/blood-2014-01-547612

Cited by 29 publications

(30 citation statements)

References 9 publications

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“…Approximately 30 years previously, Rouah et al first described the local infiltration of lymphocytes into the CNS in a study of the autopsied brains of GVHD patients (2). Similar findings have been reported in recent years using animal models of chronic GVHD (3,4). Openshaw and Grauer et al proposed the following six criteria for diagnosing CNS-cGVHD: the occurrence with chronic GVHD affecting other organs, neurological signs of CNS involvement without other explanation, corresponding brain MRI abnormalities, abnormal CSF studies (pleocytosis, elevated protein or immunoglobulin G, oligoclonal bands), a pathological brain biopsy or post-mortem examination, and a response to immunosuppressive therapy (5,6).…”

Section: Discussionsupporting

confidence: 91%

Chronic Graft-versus-host Disease Presenting with Multiple Punctate Intracranial Lesions on Contrast-enhanced Magnetic Resonance Imaging

et al. 2017

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Central nervous system graft-versus-host disease can present quite a diagnostic challenge. We herein present a case of histologically-confirmed chronic graft versus host disease (GVHD) involving the central nervous system that occurred at 19 months after peripheral blood stem cell transplantation. Cranial magnetic resonance imaging showed areas of confluent hyperintensity in the deep/subcortical white matter with multiple punctate and curvilinear gadolinium enhancements, suggesting the disruption of the blood-brain barrier. A brain biopsy revealed perivascular CD3-positive T cell infiltration around the small vessels. We propose that the detection of punctate-enhanced lesions by magnetic resonance imaging may be a useful finding that facilitates the early diagnosis of chronic GVHD involving the central nervous system.

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Section: Discussionsupporting

confidence: 91%

Chronic Graft-versus-host Disease Presenting with Multiple Punctate Intracranial Lesions on Contrast-enhanced Magnetic Resonance Imaging

et al. 2017

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“…Given the considerable inadequacies of current GVHD prevention strategies, the identification of novel targetable pathways and molecules represents one of the major challenges in the field. To propel the field past the candidate-molecule approach for the identification of new therapeutics, we have developed a non-human primate (NHP) model of GVHD(5, 6) and have used this model to perform whole transcriptome analysis of donor T cells, to identify the molecular pathways activated in these T cells during acute GVHD (GVHD). The NHP model offers several advantages compared with small animal models of GVHD, including the high degree of cross-reactivity of clinical reagents with NHP targets(7, 8), as well as the close similarity of pharmacokinetic/pharmacodynamic parameters in NHP compared to patients.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention

et al. 2015

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Graft versus host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of non-human primate (NHP) T cells during acute GVHD. Utilizing microarray technology, we measured the expression profiles of CD3+ T cells from five cohorts: allogeneic transplant recipients receiving 1) no immunoprophylaxis (No Rx); 2) sirolimus monotherapy (Siro); 3) tacrolimus-methotrexate (Tac-Mtx); as well as 4) autologous transplant recipients (Auto) and 5) healthy controls (HC). This comparison allowed us to identify transcriptomic signatures specific for allo-reactive T cells and determine the impact of both mTOR and calcineurin inhibition on GVHD-mediated pathway dysregulation. We found that the transcriptional profile of unprophylaxed GVHD was characterized by significant perturbation of pathways regulating T cell proliferation, effector function and cytokine synthesis. Within these pathways we discovered potentially druggable targets not previously implicated in GVHD, prominently including aurora kinase A (AURKA). Utilizing a murine GVHD model, we demonstrated that pharmacologic inhibition of AURKA could improve survival. Moreover, we found enrichment of AURKA transcripts both in allo-proliferating T cells and in sorted T cells from patients with clinical GVHD. These data provide a comprehensive elucidation of the T cell transcriptome in primate acute GVHD. This transcriptome enables a systems-based approach to the identification of targets for disease control, many of which are immediately amenable for clinical evaluation. The first such target identified, AURKA should now be considered a lead target for prevention of GVHD, which, given the many available AURKA inhibitors in clinical development, could be quickly deployed for the prevention of GVHD.

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“…[4][5][6] To discover the transcriptional networks that drive GVHD during clinically relevant immunoprophylaxis, we have now mapped the T-cell dysregulation that occurs in the setting of a variety of immunoprophylactic settings. We find that 2 signatures predominate: (1) a highly proliferative, cytotoxic signature that occurs during hyperacute GVHD and (2) the much more complex immune signature of breakthrough acute GVHD, which retains some T helper (Th)/T cytotoxic (Tc)1 elements, but which is predominated by an inflammatory Th/Tc17-skewed and apoptosis-resistant T-cell profile.…”

Section: Introductionmentioning

confidence: 99%

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

Furlan

Watkins

Tkachev

et al. 2016

Blood

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• The transcriptional networks controlling breakthrough acute GVHD can be mapped, and correlate closely with clinical disease.• Breakthrough acute GVHD is transcriptionally controlled by T-cell persistence, inflammation, and Th/Tc17 skewing.One of the central challenges of transplantation is the development of alloreactivity despite the use of multiagent immunoprophylaxis. Effective control of this immune suppression-resistant T-cell activation represents one of the key unmet needs in the fields of both solid-organ and hematopoietic stem cell transplant (HCT). To address this unmet need, we have used a highly translational nonhuman primate (NHP) model to interrogate the transcriptional signature of T cells during breakthrough acute graftversus-host disease (GVHD) that occurs in the setting of clinically relevant immune suppression and compared this to the hyperacute GVHD, which develops in unprophylaxed or suboptimally prophylaxed transplant recipients. Our results demonstrate the complex character of the alloreactivity that develops during ongoing immunoprophylaxis and identify 3 key transcriptional hallmarks of breakthrough acute GVHD that are not observed in hyperacute GVHD: (1) T-cell persistence rather than proliferation, (2) evidence for highly inflammatory transcriptional programming, and (3) skewing toward a T helper (Th)/T cytotoxic (Tc)17 transcriptional program. Importantly, the gene coexpression profiles from human HCT recipients who developed GVHD while on immunosuppressive prophylactic agents recapitulated the patterns observed in NHP, and demonstrated an evolution toward a more inflammatory signature as time posttransplant progressed. These results strongly implicate the evolution of both inflammatory and interleukin 17-based immune pathogenesis in GVHD, and provide the first map of this evolving process in primates in the setting of clinically relevant immunomodulation. This map represents a novel transcriptomic resource for further systems-based efforts to study the breakthrough alloresponse that occurs posttransplant despite immunoprophylaxis and to develop evidence-based strategies for effective treatment of this disease. (Blood. 2016;128(21):2568-2579

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CD8-predominant T-cell CNS infiltration accompanies GVHD in primates and is improved with immunoprophylaxis

Cited by 29 publications

References 9 publications

Chronic Graft-versus-host Disease Presenting with Multiple Punctate Intracranial Lesions on Contrast-enhanced Magnetic Resonance Imaging

Chronic Graft-versus-host Disease Presenting with Multiple Punctate Intracranial Lesions on Contrast-enhanced Magnetic Resonance Imaging

Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

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