In this issue of
Blood
,
Piper et al
find that donor T cells that secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) promote graft-versus-host disease (GVHD) by recruiting donor ...dendritic cells.
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This amplifies the activation of alloreactive T cells and increases the severity of GVHD. The authors identified GM-CSF secretion in a rare population of CD11c
+
CD4
+
T cells that express the transcription factor Bhlhe40. Piper et al showed that Bhlhe40
+
CD4
+
donor T cells are central to the development of GVHD in the gut in murine models of allogeneic bone marrow transplantation (BMT). Transplantation of either GM-CSF or Bhlhe40 knockout donor T cells resulted in significantly lower incidence of GVHD in allogeneic BMT recipients. This paper is of broad interest to hematologists and immunologists as it illuminates the role of donor T cells in activating dendritic cells and positions GM-CSF–producing T cells as a critical link between innate and adaptive immune responses.
Full text
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a ...role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2–inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.
•Ibrutinib induced a high rate of sustained responses for patients with cGVHD and inadequate response to corticosteroid-containing therapy.•This trial supported the approval of ibrutinib for treatment of adult patients with cGVHD after failure of ≥1 lines of systemic therapy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The intestinal microbiota in allogeneic bone marrow transplant (allo-BMT) recipients modulates graft-versus-host disease (GVHD), a systemic inflammatory state initiated by donor T cells that leads to ...colitis, a key determinant of GVHD severity. Indole or indole derivatives produced by tryptophan metabolism in the intestinal microbiota limit intestinal inflammation caused by diverse stressors, so we tested their capacity to protect against GVHD in murine major histocompatibility complex–mismatched models of allo-BMT. Indole effects were assessed by colonization of allo-BMT recipient mice with tryptophanase positive or negative strains of Escherichia coli, or, alternatively, by exogenous administration of indole-3-carboxaldehyde (ICA), an indole derivative. Treatment with ICA limited gut epithelial damage, reduced transepithelial bacterial translocation, and decreased inflammatory cytokine production, reducing GVHD pathology and GVHD mortality, but did not compromise donor T-cell-mediated graft-versus-leukemia responses. ICA treatment also led to recipient-strain-specific tolerance of engrafted T cells. Transcriptional profiling and gene ontology analysis indicated that ICA administration upregulated genes associated with the type I interferon (IFN1) response, which has been shown to protect against radiation-induced intestinal damage and reduce subsequent GVHD pathology. Accordingly, protective effects of ICA following radiation exposure were abrogated in mice lacking IFN1 signaling. Taken together, these data indicate that indole metabolites produced by the intestinal microbiota act via type I IFNs to limit intestinal inflammation and damage associated with myeloablative chemotherapy or radiation exposure and acute GVHD, but preserve antitumor responses, and may provide a therapeutic option for BMT patients at risk for GVHD.
•Microbiota-derived or orally administered indoles limit GVHD but not graft-versus-leukemia.•Indoles act via IFN1 signaling to protect and repair the mucosal barrier from damage.
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Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We have previously shown that NKG2C(+) NK cells from CMV naive umbilical cord blood grafts expand preferentially in recipients after CMV reactivation, representing a primary NK cell response after ...hematopoietic cell transplantation. In this study, recipients of adult donor hematopoietic cell transplantation were assessed to evaluate the role of donor/recipient CMV serostatus on the expression and function of NKG2C(+) NK cells to determine responses to secondary CMV events. Expansion of NKG2C(+) NK cells was seen following clinical CMV reactivation. However, they also expanded in the absence of detectable CMV viremia when both the donor and recipient were CMV seropositive. Upregulation of NKG2C was observed in NK cells from CMV-positive recipients receiving grafts from CMV-seropositive or -seronegative donors. These in vivo-expanded NKG2C(+) NK cells had an increased capacity for target cell-induced cytokine production, expressed an inhibitory killer Ig-like receptor for self-HLA and preferentially acquired CD57. Most importantly, NKG2C(+) NK cells transplanted from seropositive donors exhibit heightened function in response to a secondary CMV event compared with NKG2C(+) NK cells from seronegative donors. We conclude that NKG2C(+) memory-like NK cells are transplantable and require active or latent (subclinical) expression of CMV Ag in the recipient for clonal expansion of NK cells previously exposed to CMV in the donor.
The capacity to use CAR T-cell therapy has been limited by the need to produce cells in a specialized laboratory. In this study, 40% of patients with relapsed or refractory diffuse large B-cell ...lymphoma may have had durable complete responses with cells manufactured in a central commercial laboratory.
•Microbiota and their metabolites maintain immune homeostasis within the gut.•Aryl hydrocarbon receptor ligands, or indoles, modulate innate and adaptive immunity.•Indoles improve gut barrier ...integrity and protect against graft versus host disease.
Graft versus host disease is a life-threatening complication following allogeneic hematopoietic stem cell transplantation driven by donor T cells reacting against disparate host antigens. Immune homeostasis within the gut plays a major role in the graft versus host response. Gut microbiota and its metabolites impact gut integrity, inflammation and immune activation within the gut. This review will focus on the role of indoles, a product of microbiota metabolism, on gut homeostasis and our current understanding on how that modulates graft versus host disease.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this study of unrelated-donor transplantation for hematologic cancers, survival was similar with bone marrow and peripheral-blood stem-cell grafts. However, graft failure was more common with the ...former, and chronic graft-versus-host disease with the latter.
In the early days of allogeneic hematopoietic stem-cell transplantation, the only graft source available was bone marrow harvested from the pelvis of a donor under anesthesia. When studies showed that an increased dose of bone marrow cells correlated with more robust hematopoietic engraftment and lower mortality from infectious complications, transplantation centers began to use filgrastim-stimulated peripheral blood, which has a much higher content of blood progenitor cells than bone marrow, although there was concern that the higher T-cell content might increase the risk of graft-versus-host disease (GVHD).
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Several large, randomized trials of transplantation between HLA-identical siblings showed that peripheral-blood . . .
A universal vaccine against influenza would ideally generate protective immune responses that are not only broadly reactive against multiple influenza strains but also long-lasting. Because long-term ...serum antibody levels are maintained by bone marrow plasma cells (BMPCs), we investigated the production and maintenance of these cells after influenza vaccination. We found increased numbers of influenza-specific BMPCs 4 weeks after immunization with the seasonal inactivated influenza vaccine, but numbers returned to near their prevaccination levels after 1 year. This decline was driven by the loss of BMPCs induced by the vaccine, whereas preexisting BMPCs were maintained. Our results suggest that most BMPCs generated by influenza vaccination in adults are short-lived. Designing strategies to enhance their persistence will be a key challenge for the next generation of influenza vaccines.
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