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Blood Jul 2020Allogeneic hematopoietic stem cell transplantation (alloSCT) is an important curative therapy for high-risk hematological malignancies, but the development of severe... (Review)
Review
Allogeneic hematopoietic stem cell transplantation (alloSCT) is an important curative therapy for high-risk hematological malignancies, but the development of severe and/or steroid-refractory acute graft-versus-host disease (aGVHD) remains a significant limitation to optimal outcomes. New approaches to prevent and treat aGVHD remain an unmet need that can be best addressed by understanding the complex disease pathophysiology. It is now clear that chemoradiotherapy used prior to alloSCT induces the release of endogenous alarmins (eg, HMGB-1, ATP, IL-1α, IL-33) from recipient tissue. Exogenous pathogen-derived molecules (eg, lipopolysaccharide, nucleic acids) also translocate from the gastrointestinal tract lumen. Together, these danger signals activate antigen-presenting cells (APCs) to efficiently present alloantigen to donor T cells while releasing cytokines (eg, interleukin-12 [IL-12], IL-23, IL-6, IL-27, IL-10, transforming growth factor-β) that expand and differentiate both pathogenic and regulatory donor T cells. Concurrent costimulatory signals at the APC-T-cell interface (eg, CD80/CD86-CD28, CD40-CD40L, OX40L-OX40, CD155/CD112-DNAM-1) and subsequent coinhibitory signals (eg, CD80/CD86-CTLA4, PDL1/2-PD1, CD155/CD112-TIGIT) are critical to the acquisition of effector T-cell function and ensuing secretion of pathogenic cytokines (eg, IL-17, interferon-γ, tissue necrosis factor, granulocyte-macrophage colony-stimulating factor) and cytolytic degranulation pathway effectors (eg, perforin/granzyme). This review focuses on the combination of cytokine and costimulatory networks at the T-cell surface that culminates in effector function and subsequent aGVHD in target tissue. Together, these pathways now represent robust and clinically tractable targets for preventing the initiation of deleterious immunity after alloSCT.
Topics: Allografts; Animals; B7 Antigens; Cytokines; Graft vs Host Disease; Humans; Stem Cell Transplantation; T-Lymphocytes, Regulatory
PubMed: 32526028
DOI: 10.1182/blood.2019000952 -
Blood Jan 2015Chronic graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HCT). The... (Review)
Review
Chronic graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HCT). The 2-year cumulative incidence of chronic GVHD requiring systemic treatment is ~30% to 40% by National Institutes of Health criteria. The risk of chronic GVHD is higher and the duration of treatment is longer after HCT with mobilized blood cells than with marrow cells. Clinical manifestations can impair activities of daily living and often linger for years. Hematology and oncology specialists who refer patients to centers for HCT are often subsequently involved in the management of chronic GVHD when patients return to their care after HCT. Treatment of these patients can be optimized under shared care arrangements that enable referring physicians to manage long-term administration of immunosuppressive medications and supportive care with guidance from transplant center experts. Keys to successful collaborative management include early recognition in making the diagnosis of chronic GVHD, comprehensive evaluation at the onset and periodically during the course of the disease, prompt institution of systemic and topical treatment, appropriate monitoring of the response, calibration of treatment intensity over time in order to avoid overtreatment or undertreatment, and the use of supportive care to prevent complications and disability.
Topics: Allografts; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Incidence; Male
PubMed: 25398933
DOI: 10.1182/blood-2014-08-551994 -
FASEB Journal : Official Publication of... Mar 2019Immunodeficient mice engrafted with human peripheral blood mononuclear cells (PBMCs) support preclinical studies of human pathogens, allograft rejection, and human...
Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression.
Immunodeficient mice engrafted with human peripheral blood mononuclear cells (PBMCs) support preclinical studies of human pathogens, allograft rejection, and human T-cell function. However, a major limitation of PBMC engraftment is development of acute xenogeneic graft- versus-host disease (GVHD) due to human T-cell recognition of murine major histocompatibility complex (MHC). To address this, we created 2 NOD- scid IL-2 receptor subunit γ ( IL2rg) (NSG) strains that lack murine MHC class I and II [NSG-β-2-microglobulin ( B2M) ( IA IE) and NSG -( K D) ( IA)]. We observed rapid human IgG clearance in NSG- B2M ( IA IE) mice whereas clearance in NSG -( K D) ( IA) mice and NSG mice was comparable. Injection of human PBMCs into both strains enabled long-term engraftment of human CD4 and CD8 T cells without acute GVHD. Engrafted human T-cell function was documented by rejection of human islet allografts. Administration of human IL-2 to NSG -( K D) ( IA) mice via adeno-associated virus vector increased human CD45 cell engraftment, including an increase in human regulatory T cells. However, high IL-2 levels also induced the development of GVHD. These data document that NSG mice deficient in murine MHC support studies of human immunity in the absence of acute GVHD and enable evaluation of human antibody therapeutics targeting human T cells.-Brehm, M. A., Kenney, L. L., Wiles, M. V., Low, B. E., Tisch, R. M., Burzenski, L., Mueller, C., Greiner, D. L., Shultz, L. D. Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression.
Topics: Animals; Female; Genes, MHC Class I; Genes, MHC Class II; Graft Survival; Graft vs Host Disease; Heterografts; Humans; Islets of Langerhans Transplantation; Leukocytes, Mononuclear; Male; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Phenotype; T-Lymphocytes
PubMed: 30383447
DOI: 10.1096/fj.201800636R -
Biology of Blood and Marrow... Jan 2016Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical...
Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation.
Topics: Acute Disease; Allografts; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Practice Guidelines as Topic; Randomized Controlled Trials as Topic
PubMed: 26386318
DOI: 10.1016/j.bbmt.2015.09.001 -
Blood Advances Aug 2018Treatment of severe aplastic anemia has improved significantly over the past 4 decades. This review will summarize the key areas of progress in the use of allogeneic... (Review)
Review
Treatment of severe aplastic anemia has improved significantly over the past 4 decades. This review will summarize the key areas of progress in the use of allogeneic hematopoietic cell transplantation and nontransplant immunosuppressive therapy (IST) for the treatment of aplastic anemia and then summarize the recommendations for first-line treatment. Based on recent data, we argue that guidelines for the initial treatment of patients with newly diagnosed severe aplastic anemia require revision. At the time of diagnosis, before beginning treatment, HLA typing should be done to identify a marrow donor among family members or in the unrelated donor registries, and a marrow transplant should be considered first-line therapy. The priority order of donor source for bone marrow transplantation is: (1) HLA-identical sibling, (2) HLA-matched unrelated donor, and (3) HLA-haploidentical donor if an HLA-matched unrelated donor is not rapidly available. Each of these donor marrow sources may be preferable to nontransplant IST. We make this recommendation because of the long-term persistent risk for disease relapse and secondary myelodysplastic syndrome or acute myeloid leukemia with the use of nontransplant IST for patients with aplastic anemia. In contrast, marrow transplantation is associated with high cure rates of aplastic anemia and a relatively low risk for graft-versus-host disease, with many patients now living for decades without the risk for disease recurrence or the development of clonal disorders. Implementation of this first-line treatment strategy will provide patients with severe aplastic anemia the best chance of long-term disease-free survival.
Topics: Allografts; Anemia, Aplastic; Bone Marrow Transplantation; Donor Selection; Histocompatibility Testing; Humans; Unrelated Donors
PubMed: 30108110
DOI: 10.1182/bloodadvances.2018021162 -
International Journal of Hematology Sep 2013Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective form of tumor immunotherapy available to date and the frequency of transplants... (Review)
Review
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective form of tumor immunotherapy available to date and the frequency of transplants continues to increase worldwide. However, while allo-HSCT usually induces a beneficial graft-versus leukemia effect, a major source of morbidity and mortality following allo-HSCT is graft-versus-host disease (GVHD). Currently available diagnostic and staging tools frequently fail to identify those at higher risk for GVHD morbidity, treatment unresponsiveness, and death. Furthermore, there are shortcomings in the risk stratification of patients before GVHD clinical signs develop. In parallel, recent years have been characterized by an explosive evolution of omics technologies, largely due to technological advancements in chemistry, engineering, and bioinformatics. Building on these opportunities, plasma biomarkers have been identified and validated as promising diagnostic and prognostic tools for acute GVHD. This review summarizes current information on the types of GVHD biomarkers, the omics tools used to identify them, the biomarkers currently validated as acute GVHD markers, and future recommendations for incorporating biomarkers into new grading algorithms for risk-stratifying patients and creating more personalized treatment courses. Future directions will include randomized evaluations of these biomarkers in multicenter prospective studies while extending on the need for biomarkers of chronic GVHD.
Topics: Acute Disease; Allografts; Biomarkers; Chronic Disease; Graft vs Host Disease; HLA Antigens; Hematopoietic Stem Cell Transplantation; Humans; MicroRNAs; Polymorphism, Single Nucleotide; Precision Medicine; Prognosis; Proteomics; T-Lymphocytes, Regulatory
PubMed: 23959582
DOI: 10.1007/s12185-013-1406-9 -
Frontiers in Immunology 2018Allogeneic stem cell transplantation (allo-SCT) is a curable method for the treatment of hematological malignancies. In the past two decades, the establishment of... (Review)
Review
Allogeneic stem cell transplantation (allo-SCT) is a curable method for the treatment of hematological malignancies. In the past two decades, the establishment of haploidentical transplant modalities make "everyone has a donor" become a reality. However, graft-versus-host disease (GVHD) and relapse remain the major two causes of death either in the human leukocyte antigen (HLA)-matched transplant or haploidentical transplant settings, both of which restrict the improvement of transplant outcomes. Preclinical mice model showed that both donor-derived T cells and natural killer (NK) cells play important role in the pathogenesis of GVHD and the effects of graft-versus-leukemia (GVL). Hence, understanding the immune mechanisms of GVHD and GVL would provide potential strategies for the control of leukemia relapse without aggravating GVHD. The purpose of the current review is to summarize the biology of GVHD and GVL responses in preclinical models and to discuss potential novel therapeutic strategies to reduce the relapse rate after allo-SCT. We will also review the approaches, including optimal donor selection and, conditioning regimens, donor lymphocyte infusion, BCR/ABL-specific CTL, and chimeric antigen receptor-modified T cells, which have been successfully used in the clinic to enhance and preserve anti-leukemia activity, especially GVL effects, without aggravating GVHD or alleviate GVHD.
Topics: Allografts; Animals; Clinical Trials as Topic; Disease Models, Animal; Donor Selection; Graft vs Host Disease; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunotherapy, Adoptive; Killer Cells, Natural; Leukemia; Mice; Neoplasm Recurrence, Local; Receptors, Chimeric Antigen; T-Lymphocytes; Transplantation Conditioning; Transplantation, Homologous
PubMed: 30619371
DOI: 10.3389/fimmu.2018.03041 -
Biology of Blood and Marrow... Dec 2019In clinical trials of chronic graft-versus-host disease (cGVHD), the need to start a new systemic treatment is considered a treatment failure. A composite endpoint... (Clinical Trial)
Clinical Trial Observational Study
In clinical trials of chronic graft-versus-host disease (cGVHD), the need to start a new systemic treatment is considered a treatment failure. A composite endpoint called "failure-free survival" (FFS), where events are initiation of a new systemic cGVHD treatment, recurrent malignancy, and death, has been suggested as a possible long-term indicator of success. The goal of the current study was to identify changes in cGVHD manifestations from baseline to 6 months that could accurately predict subsequent longer-term FFS, thereby making it possible to assess outcomes earlier than would otherwise be possible. We used data from 2 prospective, multicenter, observational studies to develop the cGVHD-FFS index. The cGVHD-FFS index was calculated at 6 months, a typical timepoint for assessment of the primary endpoint of phase II cGVHD trials. Subsequent FFS was only 45% within the next 2 years. We found that changes in the scores for the eyes, joint/fascia, and mouth ulcers from baseline to 6 months were associated with subsequent FFS, but the prognostic accuracy of these changes was not adequate for use in trials. Biomarker studies might help to identify criteria that improve prediction of long-term clinical outcomes in patients with cGVHD.
Topics: Adolescent; Adult; Aged; Allografts; Child; Child, Preschool; Chronic Disease; Disease-Free Survival; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Prospective Studies; Survival Rate
PubMed: 31394265
DOI: 10.1016/j.bbmt.2019.07.040 -
Biology of Blood and Marrow... Dec 2019Vulvovaginal graft-versus-host disease (GVHD) is an underdiagnosed and poorly recognized complication of hematopoietic stem cell transplantation (HSCT). Previous studies... (Clinical Trial)
Clinical Trial
Vulvovaginal graft-versus-host disease (GVHD) is an underdiagnosed and poorly recognized complication of hematopoietic stem cell transplantation (HSCT). Previous studies have reported findings restricted to predominantly adult populations. We report a case series of pediatric and young adult vulvovaginal GVHD, which was identified in 19 patients (median age, 11.8 years; range, 2.4 to 21.9 years) out of a total 302 female patients who underwent transplantation over an 8-year period at a pediatric HSCT center. The majority of patients had concomitant nongenital GVHD; only 1 patient had isolated vulvovaginal GVHD. The median time from bone marrow transplantation to diagnosis of vulvovaginal GVHD was 30 months (range, 2.3 to 97.5 months). A high percentage of the patients in our series were without vulvar or vaginal symptoms (n = 8; 42%), even though 17 patients (89%) presented with grade 3 disease based on current adult grading scales. Vulvar examination findings most frequently included interlabial and clitoral hood adhesions (89%), loss of architecture of the labia minora or clitoral hood (42%), and skin erosions or fissures (37%). Only 5 patients underwent a speculum exam, none of whom had vaginal GVHD. Examination findings of primary ovarian insufficiency (POI) can overlap with those of GVHD, and 6 patients (32%) in our cohort were diagnosed with POI. Only 1 patient was on systemic hormone replacement therapy at the time of vulvovaginal GVHD diagnosis. The majority of patients (n = 16) were treated with topical steroid therapy, with a median time to response of 43 days. Five patients (26%) had a complete response to therapy, and 10 patients (53%) had a partial response. This case series provides valuable insight into pediatric and young adult vulvovaginal GVHD and highlights the need for increased screening for vulvar disease in this population.
Topics: Adolescent; Adult; Allografts; Child; Child, Preschool; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Ovarian Diseases; Vaginal Diseases; Vulvar Diseases; Young Adult
PubMed: 31325588
DOI: 10.1016/j.bbmt.2019.07.015 -
Expert Review of Clinical Immunology May 2018Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation... (Review)
Review
Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an increasingly applied curative method for both benign and malignant hematologic disorders. Biomarker identification is crucial for the development of noninvasive and cost-effective cGVHD diagnostic, prognostic, and predictive test for use in clinic. Furthermore, biomarkers may help to gain a better insight on ongoing pathophysiological processes. The recent widespread application of omics technologies including genomics, transcriptomics, proteomics and cytomics provided opportunities to discover novel biomarkers. Areas covered: This review focuses on biomarkers identified through omics that play a critical role in target identification for drug development, and that were verified in at least two independent cohorts. It also summarizes the current status on omics tools used to identify these useful cGVHD targets. We briefly list the biomarkers identified and verified so far. We further address challenges associated to their exploitation and application in the management of cGVHD patients. Finally, insights on biomarkers that are drug targetable and represent potential therapeutic targets are discussed. Expert commentary: We focus on biomarkers that play an essential role in target identification.
Topics: Allografts; Animals; Biomarkers; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Prognosis
PubMed: 29629613
DOI: 10.1080/1744666X.2018.1463159