scholarly journals Immunoregulatory effect of mouse fetal neural cells on the graft-versus-host disease

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
A. Goltsev ◽  
N. Babenko ◽  
Yu. Gaevska ◽  
T. Dubrava ◽  
O. Lutsenko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Relative Number ◽  
Neural Cells ◽  
Host Disease ◽  
Foxp3 Gene ◽  
Graft Versus Host ◽  
Gene Transcripts ◽  
Control Injection

The problem of the treatment of acute and chronic graft-versus-host disease (GVHD), when histoincompatible bone marrow (BM) is used, remains unsolved. An important role in controlling the development of GVHD is played by Treg immunity.The purpose of the study is to evaluate the immunoregulatory effect of native and cryopreserved murine fetal neural cells (FNCs) relative to Treg immunity of mice with GVHD.Materials and methods. Acute GVHD was induced by the injection of histoincompatible BM to lethally irradiated mice. On the 14th day after GVHD induction and transplantation of native or cryopreserved FNCs in animals of all experimental groups, the spleen index, the content of T-regulatory (FOXP3+) cells and the number of foxp3 gene transcripts in the СD4+splenocytes were determined.Results. The recipients of the histoincompatible BM had a decrease in the content of T-reg cells and the level of foxp3 gene expression in the splenocyte population relative to the syngeneic control. Injection of native or cryopreserved FNCs to animals with GVHD caused an increase in the number of T-reg cells. Cryopreserved FNCs are more than native ones enhancing both the relative number of T-reg cells and the level of foxp3 gene expression in the splenocytes, which was characterized by a higher recipients’ survival up to the 16th day of observation.Conclusion. The transplantation of fetal neural cells to recipients with GVHD stimulates the Treg immunity, which is a key to the development of immune conflict. This confirms the possibility of using fetal neural cells as a therapeutic immuno-regulatory agent.

The Impact of Age and Body Fat on Graft-Versus-Host Disease (GVHD) in Mice

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1100-1100
Author(s):  
Chien-Chun Steven Pai ◽  
Mingyi Chen ◽  
Lam Khuat ◽  
Annie Mirsoian ◽  
Anthony E Zamora ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Fat ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Obese Mice ◽  
Gi Tract ◽  
Host Disease ◽  
Graft Versus Host ◽  
Aged Mice ◽  
Tnf Α

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative procedure performed for a variety of hematological diseases. Patient populations undergoing HSCT are generally skewed towards either young or old age due to the pathogenesis of hematological cancers. Several retrospective studies have identified age as one of the risk factors that correlate with treatment related mortality (TRM), graft versus host disease (GVHD) and tumor relapse. Aging is characterized by a gradual decline in immune cell function, known as immune senescence, yet is also hallmarked by a chronic, low-grade proinflammatory phenotype termed “inflammaging”. We hypothesized that aged animals develop more severe GVHD as a result of this inflammaging phenomenon. To investigate this, we first transplanted donor cells from B10.D2 mice (H-2d) into either young (< 3 months old) or aged (>15 months old) BALB/c (H-2d) recipients. While young recipients developed typical sclerodermatous chronic GVHD and died by 56 days post transplantation, aged mice developed severe acute GVHD and died at Day 7. Upon pathological examination, aged mice displayed massive lymphocytic infiltration associated with tissue necrosis in the gastrointestinal (GI) tract. Among several cytokines examined, elevated levels of serum TNF-α (97.89±9.83 versus 68.29±1.07 pg/ml, respectively) were observed in aged animals compared to young counterparts. Similarly, TNF-α and IL-6 gene expression levels were also increased in GI tract tissues. Additionally, we found greater frequencies of splenocyte derived TNF-α+ macrophages (CD45+CD19-F4/80+/CD11b+) in aged animals compared to young animals (26.2±1.00% versus 17.233±1.25%, respectively; P< 0.001) following allogeneic HSCT. Macrophage depletion using liposomal clodronate reduced serum TNF-α levels (97.89 ±9.83 versus 57.17±2.86 pg/ml) in aged mice following HSCT. We observed that aged mice had markedly higher levels of visceral body fat compared to young mice. Based on the similarities in the inflammatory status between aged and obese animals, we next sought to verify whether the severity of GVHD can also be attributed to obesity. Eight week old recipient BALB/c mice were maintained on either a low fat diet (10% calories from fat) or a high fat diet (60% calories from fat) for three months. Each cohort of mice then underwent HSCT, following a conditional regimen of total body irradiation (Cs; 800 cGy) and adoptive transfer from donor B10.D2 mice. In line with the results observed from aged recipients, diet induced obese (DIO) mice died at Day 7 and demonstrated a severe acute GVHD response in the GI tract compared to lean mice based on histo-pathological scores correlating with significantly increased TNF-α and IL-6 gene expression in the GI tract. Flow analysis revealed an increase in total numbers of CD8+ T cells infiltrating in the GI tract in obese mice compared to lean mice (0.229± 0.025 x 106 versus 0.071± 0.010 x 106; P<0.01). In addition, obese mice demonstrated an increase in total numbers of TNF-a+ macrophages (CD45+F4/80+CD11b+TNF-α +; 5.18± 1.09 x 104 versus 1.31± 0.75 x 104 ; P<0.05) in the visceral fat tissues. Overall, these data implicate that age and body fat can predispose to severe acute GVHD, which is associated with increased production of proinflammatory cytokines mediated by dysregulated macrophages. Disclosures No relevant conflicts of interest to declare.

scholarly journals FOXP3 gene expression value in regulatory T cells in pathogenesis of graft-versus-host disease induced with cryopreserved allogenic material

2014 ◽  
Vol 24 (4) ◽  
pp. 322-331 ◽  
Author(s):  
Anatoliy N. Goltsev ◽  
◽  
Tatuyana G. Dubrava ◽  
Yuliya A. Gayevskaya ◽  
Elena D. Lutsenko ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Foxp3 Gene ◽  
Graft Versus Host

scholarly journals Acute and chronic graft versus host disease after hematopoietic stem cell transplant

JBMTCT ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. 53-66
Author(s):  
Vaneuza A. M. Funke ◽  
Maria Claudia Rodrigues Moreira ◽  
Afonso Celso Vigorito
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Primary Therapy ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Graft versus host disease is one of the main complications of Hematopoietic stem cell, in­volving about 50% to 80% of the patients. Acute GVHD clinical manifestations and therapy is discussed, as well as new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both refractory chronic and acute GVHD is an important field of discussion once there is no superiority for the majority of the agents after primary therapy has failed. Hence, this review is meant to be a useful tool of consultation for clinicians who are dealing with this complex complication.

scholarly journals The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Ronjon Chakraverty ◽  
Megan Sykes
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Tissue Injury ◽  
Chronic Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells ◽  
Antigen Presenting

After allogeneic blood or bone marrow transplantation, donor T cells interact with a distorted antigen-presenting cell (APC) environment in which some, but not all, host APCs are replaced by APCs from the donor. Significantly, host APCs are required for the priming of acute graft-versus-host disease (GVHD). Donor APCs play a lesser role in the induction of acute GVHD despite their predicted capacity to cross-present host antigens. In contrast, donor APCs may play a role in perpetuating the tissue injury observed in chronic GVHD. Host APCs are also required for maximal graft-versus-leukemia responses. Recent studies have suggested potential strategies by which the continued presence of host APCs can be exploited to prime strong donor immunity to tumors without the induction of GVHD.

scholarly journals Signaling Through the Type 2 Cannabinoid Receptor Regulates the Severity of Acute and Chronic Graft versus Host Disease

Blood ◽  
2020 ◽  
Author(s):  
Cheng Yin Yuan ◽  
Vivian Zhou ◽  
Garrett Sauber ◽  
Todd M Stollenwerk ◽  
Richard Komorowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Acute Gvhd ◽  
Cannabinoid Receptor ◽  
Therapeutic Targeting ◽  
Host Disease ◽  
Graft Versus Host

Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R) which is expressed on nearly all immune cells and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells, or administration of a selective CB2R pharmacological antagonist, exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T cell alloreactivity. Using a novel CB2R-EGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions. Therapeutic targeting of the CB2R with the agonists, tetrahydrocannabinol (THC) and JWH-133, revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contribute to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and ERK phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase. These studies demonstrate that the CB2R plays a critical role in the regulation of GVHD and suggest that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.

Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1572-1579 ◽  
Author(s):  
Franco Locatelli ◽  
Marco Zecca ◽  
Roberto Rondelli ◽  
Federico Bonetti ◽  
Giorgio Dini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Acute Leukemia ◽  
Graft Versus Host Disease ◽  
Cyclosporine A ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Leukemia Relapse

Leukemia relapse is a major cause of treatment failure for patients with acute leukemia given allogeneic bone marrow transplantation (BMT). This study evaluated whether a reduction of the dosage of cyclosporine-A (Cs-A) used for graft versus host disease (GVHD) prophylaxis could reduce relapse rate (RR) in children with acute leukemia given BMT. Fifty-nine children who had transplantation from HLA-identical siblings were randomized to receive Cs-A intravenously at a dosage of 1 mg/kg/d (Cs-A1) or of 3 mg/kg/d (Cs-A3) until patients were able to tolerate oral intake. Subsequently, both groups received Cs-A orally at a dosage of 6 mg/kg/d, with discontinuation 5 months after BMT. The probability of developing grade II-IV acute GVHD was 57% for the Cs-A1 group versus 38% for the Cs-A3 group (P = .06); the probability of developing chronic GVHD was 30% for the Cs-A1 group and 26% for the Cs-A3 group (P = NS). Three patients died of grade IV acute GVHD: 2 were in the Cs-A1 and the third in the Cs-A3 group. The RR was 15% for the Cs-A1 group and 41% for the Cs-A3 group (P = .034); 1-year transplant-related mortality estimates were 17% and 7%, respectively (P = NS). With a median observation time of 44 months from BMT, the 5-year event-free survival for children belonging to Cs-A1 and Cs-A3 groups was 70% and 51%, respectively (P = .15). Our data demonstrate that the use of low Cs-A doses is associated with a statistically significant reduction of leukemia relapse, probably due to an increased graft versus leukemia effect.

scholarly journals Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia [published erratum appears in Blood 1989 Aug 15;74(3):1180]

Blood ◽  
1989 ◽  
Vol 73 (6) ◽  
pp. 1720-1728 ◽  
Author(s):  
KM Sullivan ◽  
PL Weiden ◽  
R Storb ◽  
RP Witherspoon ◽  
A Fefer ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Blast Crisis ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Host Disease ◽  
Graft Versus Host

Abstract To assess the influence of graft-versus-host disease (GVHD) on recurrent leukemia and survival after allogeneic marrow transplantation, we studied 1,202 patients with acute nonlymphocytic leukemia (ANL), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML) given unmodified marrow grafts from HLA- identical siblings. Proportional hazards regression models using acute GVHD and chronic GVHD as time-dependent covariates demonstrated a significant association of GVHD with a decreased relative risk (RR, 0.33 to 0.42) of relapse in patients with ANL, ALL, and CML transplanted in advanced disease. Among patients developing either acute or chronic GVHD, treatment failure (that is, mortality or relapse) was decreased in patients with ALL transplanted in relapse (RR = 0.70, P less than .033) and CML in blast crisis (RR = 0.37, P less than .009). This effect was independent of age, sex, preparative regimen, GVHD prophylaxis, or length of follow-up. Five-year actuarial estimates were derived for the subset of 657 patients who survived in remission 150 days after transplant and were at risk for development of chronic GVHD. Among patients with ANL in first remission or CML in chronic phase, GVHD had an adverse effect on survival and no apparent influence on relapse. Among patients with ANL and ALL transplanted in relapse, the probability of relapse after day 150 was 74% without [corrected] GVHD, 45% with acute and chronic GVHD, 35% with [corrected] only acute GVHD, and 34% with only chronic GVHD (P less than .001). Actuarial survival in these four GVHD groups was 25%, 34%, 59%, and 62%, respectively (P less than .009). Among patients with CML in acceleration or blast crisis, the probability of relapse after day 150 was 65% without GVHD and 36% with acute and/or chronic GVHD (P less than .017). We conclude that acute and chronic GVHD were associated with a durable antileukemic effect and improved survival in patients transplanted in advanced stages of ALL and CML.

scholarly journals Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria

Blood ◽  
2019 ◽  
Vol 134 (3) ◽  
pp. 304-316 ◽  
Author(s):  
Geoffrey D. E. Cuvelier ◽  
Eneida R. Nemecek ◽  
Justin T. Wahlstrom ◽  
Carrie L. Kitko ◽  
Victor A. Lewis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Bronchiolitis Obliterans Syndrome ◽  
National Institutes Of Health ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Nih Consensus Criteria ◽  
Adjudication Committee

Abstract Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients &lt;18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients &lt;18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.

scholarly journals Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1342-1348 ◽  
Author(s):  
JH Antin ◽  
HJ Weinstein ◽  
EC Guinan ◽  
P McCarthy ◽  
BE Bierer ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Response To Therapy ◽  
Mrna Levels ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host

Abstract Acute graft-versus-host disease (GVHD) that is resistant to therapy is a highly lethal complication of marrow transplantation. Inflammatory cytokines such as interleukin-1 (IL-1) may be critical mediators of this process. If so, specific inhibition of IL-1 activity with recombinant human IL-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1, may ameliorate acute GVHD. We performed an open-label, phase I/II trial to evaluate the safety and efficacy of IL-1Ra in 17 patients with steroid-resistant GVHD. The IL- 1Ra was administered as a 24-hour continuous infusion over 7 days. The dose was escalated in cohorts of patients from 400 to 3,200 mg/d. Acute GVHD was evaluated in each affected organ and as an overall grade. Stage-specific improvement of acute GVHD occurred in the skin (8 of 14, 57%), gut (9 of 11, 82%), and liver (2 of 11, 18%). Overall, acute GVHD improved by at least one grade in 10 of 16 (63%) patients. Response to therapy was associated with a reduction of tumor necrosis factor-alpha (TNF-alpha) mRNA levels in blood mononuclear cells (P = .001). The only toxicity attributable to IL-1Ra was reversible transaminase elevation in two patients. Inhibition of IL-1 activity with IL-1Ra is safe and has demonstrable efficacy in acute GVHD that failed to respond to conventional treatment. These data provide further evidence that IL-1 is a mediator of GVHD.

scholarly journals Predictive factors for acute graft-versus-host disease in patients transplanted with HLA-identical bone marrow

Blood ◽  
1984 ◽  
Vol 63 (6) ◽  
pp. 1265-1270 ◽  
Author(s):  
DS Bross ◽  
PJ Tutschka ◽  
ER Farmer ◽  
WE Beschorner ◽  
HG Braine ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Host Disease ◽  
Graft Versus Host ◽  
Predictive Parameters ◽  
Clinically Significant ◽  
Mismatched Donor ◽  
Acute Graft

Abstract To identify predictive parameters for incidence and severity of acute graft-versus-host disease (GVHD), 136 patients, transplanted with histocompatible marrow as therapy for aplastic anemia and hematologic malignancies, were examined using univariate and multivariate analyses. The risk of GVHD increased in patients with acute lymphocytic leukemia (p less than 0.05), in sex-mismatched donor-recipient pairs (p less than 0.01), and in patients older than 23.7 yr (p less than 0.05). No other commonly observed factors appeared to have any relationship to GVHD except the presence of certain alleles. The presence of a Cw4 allele or of the Bw21 specificities B49 and B50 were associated with significantly increased risks of GVHD (p less than 0.05), whereas the presence of Aw19 (or the related specificities A29, Aw30, Aw31 , Aw32, Aw33 ) was associated with a significantly decreased risk (p less than 0.01). Using these factors, a regression equation can be constructed that estimates the risk of a given patient to develop clinically significant acute GVHD.

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