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.

Infliximab for the Treatment of Chronic Graft Versus Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2889-2889
Author(s):  
Ethan Tolbert ◽  
Ned Waller ◽  
H. Jean Khoury ◽  
Mary Jo Lechowicz ◽  
Christopher Flowers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Survival ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Response Rate ◽  
The Other ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Steroid Refractory

Abstract Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity and non relapse mortality after allogeneic stem cell transplantation. Tumor necrosis factor alpha (TNF-α) is a cytokine involved in the pathogenesis of GVHD. Infliximab is a murine-human chimeric monoclonal antibody that binds TNF-α, preventing interaction with its receptor and its ability to mediate the development of GVHD. Infliximab is active in the treatment of steroid refractory acute GVHD, particularly for patients with GI GVHD (Couriel et al Blood. 2004 Aug 1;104(3):649–54).We performed a retrospective analysis to evaluate the activity of infliximab in 22 patients with AML/MDS (n=5), lymphoma (n=8), ALL (n=3), and others (n=6) with steroid refractory chronic extensive GVHD. Response was measured according to standard response criteria (Pavletic et al. Biology of Blood and Marrow Transplantation 2006 Mar;12(3):252–66). The median age of the patients was 50 years (range 20 – 64). Fourteen (64%) patients had matched sibling donors, 8 (36%) had matched unrelated donors, 9 (41%) underwent nonmyeloablative conditioning, one patient had a bone marrow transplant and the other 21 patients had peripheral blood stem cell transplants. All patients were given standard doses of tacrolimus or cyclosporine for GVHD prophylaxis with either short course methotrexate or mycophenolate mofetil. All patients were treated with systemic steroids at the onset of GVHD. Fifty percent of the patients initially presented with acute GVHD that progressed to chronic extensive GVHD. The other half presented with late onset or de novo chronic extensive GVHD. Nineteen had skin involvement (86%), 15 (68%) had gastrointestinal involvement, and 10 (45%) had liver involvement at the time of treatment with infliximab. All patients were considered refractory to tacrolimus/cyclosporine and systemic steroids, had intolerable side effects from steroids or could not be successfully tapered off steroids prior to infliximab administration. Median time from transplant to infliximab administration was 337days (range 122 to 932 days). The patients received a median of 4 weekly courses (range 1–20 courses) of infliximab at 10mg/kg. The overall response rate was 64% (n=14); 11 (50%) experienced a complete response (CR); 3 (14%) experienced a partial response (PR); 8 (36%) had progressive GVHD. The response rate for skin GVHD was 68%, GI was 60% and liver was 50%. One patient suffered an acute infusion reaction after the first infliximab dose and had no further drug administered. Median survival of all patients following initiation of infliximab was 223 days. Median survival of all responders was 625 days after infliximab, while median survival of the non-responders was 70 days after infliximab. Six patients remain alive at a median follow-up of 55 months (27%). Three of six survivors are on minimal immunosuppression with limited cGVHD and three are off all immunosuppression with no evidence of cGVHD. Of the patients who died, 7 (32%) died from infectious complications, 5 (23%) died from complications of progressive cGVHD, 4 (18%) died from hemorrhagic or embolic strokes, 2 died from complications of post-transplant lymphoproliferative disorder (PTLD), and one patient from relapse. In conclusion, infliximab has activity for cGVHD. Prospective trials investigating the activity of infliximab, the infectious risks, predictive measures responding patients and optimal timing of administration are needed.

scholarly journals Regenerating Islet-Derived 3-alpha is a Prognostic Biomarker for Gastrointestinal Chronic Graft-Versus-Host Disease

2022 ◽  
Author(s):  
Brittany Paige DePriest ◽  
Hong Li ◽  
Alan Bidgoli ◽  
Lynn Onstad ◽  
Daniel R. Couriel ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Plasma Concentrations ◽  
Gi Tract ◽  
Host Disease ◽  
Graft Versus Host ◽  
Biomarker Validation

Prognostic biomarkers used to identify likelihood of disease progression have not been identified for chronic graft-versus-host disease (cGVHD), the leading cause of late non-relapse mortality (NRM) in survivors of allogenic hematopoietic cell transplantation. Gastrointestinal cGVHD (GI-cGVHD) has been particularly challenging to classify. Here, we analyzed three proteomics markers [Regenerating-islet-derived-3-alpha (Reg3α), C-X-C-motif-ligand (CXCL9) and Stimulation-2 (ST2)] in two independent cohorts of patients with cGVHD totaling 289 patients. Plasma concentrations of Reg3α were significantly increased in patients with GI-cGVHD compared to those without (p=0.0012, p=0.01 respectively), CXCL9 and ST2 were not. Patients with high Reg3α (≥72ng/mL) vs. low Reg3α had higher NRM (23% vs. 11%, p=0.015). Since Reg3α has been identified as a lower GI-tract marker in acute GVHD, we correlated Reg3α with lower acute-like GI-cGVHD vs. classical fibrotic-like esophageal manifestations and found Reg3a did not differ between the subtypes. No difference was observed between upper and lower subtypes. Patients with extremely high Reg3α (≥180 ng/mL) had higher GI-scores but not higher lower-GI-scores. In multivariate Cox regression model, patients with high Reg3α were 1.9 times more likely to die without relapse. Our findings demonstrate the utility of Reg3α as a prognostic marker for GI-cGVHD. These data warrant prospective biomarker validation studies.

Characterization of Chronic Graft-Versus-Host Disease and Duration of Immunosuppression After Cord Blood Transplantation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4077-4077
Author(s):  
Laura F Newell ◽  
Mary E.D. Flowers ◽  
Ted Gooley ◽  
Filippo Milano ◽  
Paul A. Carpenter ◽  
...  
Keyword(s):  
Cord Blood ◽  
Median Time ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Cell Transplant ◽  
Gi Tract ◽  
Reduced Intensity Conditioning ◽  
Host Disease ◽  
Graft Versus Host ◽  
Reduced Intensity

Abstract Abstract 4077 Background: The reported incidence of chronic graft-versus-host disease (cGVHD) after cord blood transplant (CBT) varies widely in the literature, with some studies suggesting that cGVHD is more responsive to treatment after CBT than after conventional hematopoietic cell transplant (HCT). The 2005 National Institutes of Health (NIH) consensus criteria were designed to standardize the diagnosis and scoring of cGVHD. While these criteria have been used to evaluate GVHD after bone marrow (BMT) and mobilized blood (PBSCT) cell transplantation, analysis of GVHD after CBT by NIH criteria has been limited. We report the results of a single-center, prospective analysis of GVHD evaluated according to the NIH diagnostic criteria in adults and children receiving unrelated CBT after high or reduced-intensity conditioning. Methods: Eighty-seven consecutive patients who received a first single or double CBT between 2006 and 2011 were included. GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Grafts were HLA-typed at the antigen level for HLA-A and B, and high resolution for HLA-DRB1. Patients were prospectively evaluated for GVHD at day 80, 1-year, and at any other time as clinically indicated. Results: Median patient age was 31 years (range 0.8–70). Diagnosis at transplant included AML (n=49), ALL (n=20), CML (n=5), MDS/MPD (n=5), and other hematologic malignancy (n=8). The median follow-up after CBT was 24 months (range 1–127). Most patients received high-intensity conditioning (79%, n=69) and a double CB graft (86%, n=75). HLA-matching was 4/6 in 59% (n=51) of patients, 5/6 in 37% (n=32), and 6/6 in 4% (n=4). Median total infused cell doses were: 3.8 × 107 TNC/kg, 0.21 × 106 CD34+ cells/kg, and 10.9 × 106 CD3+ cells/kg. Neutrophil engraftment occurred in 90% of patients (n=78), at a median of 22 and 13 days after high and reduced-intensity conditioning, respectively. The cumulative incidence (CI) of grades II-IV and III-IV acute GVHD (aGVHD) was 74.7% and 29.9%, respectively. Sixty-eight patients (78%) were alive, engrafted with donor cells, and without relapse at day 80. Fifty-four patients had GVHD requiring systemic immunosuppressive treatment after day 80, for an estimated 2-year CI of 64%. Most patients had quiescent or interrupted onset (69%) and 48% had thrombocytopenia at time of diagnosis. By NIH criteria, 25 patients presented with “late” acute GVHD, and 29 presented with NIH cGVHD. Two patients who presented with “late” acute GVHD subsequently developed NIH cGVHD (Figure 1). Most patients with “late” acute GVHD had recurrent acute GVHD (n=20) with a median onset at 141 days after CBT (range 77–599). Organs affected by “late” acute GVHD were the GI tract (n=17), skin (n=12), and liver (n=5). Of the 31 patients with NIH cGVHD, 7 developed only the classic subtype with a median onset at 123 days after CBT (range 91–363). Organs affected in patients with classic NIH cGVHD were mouth (n=5), skin (n=5), lung (n=1), serosa (n=2), and genital (n=1). Most patients with NIH cGVHD had the overlap subtype (n=24), occurring at a median of 114 days after CBT (range 80–412). Organs involved in the overlap subtype included the GI tract (n=22), liver (n=7), acute skin (n=9), chronic skin (n=6), mouth (n=21), eyes (n=3), lung (n=1), esophagus (n=1), and serosa (n=3). The estimated 3-year CI of discontinuing immunosuppressive therapy (IST) while alive without relapse was 52%, while the 3-year estimated CI of death or relapse during IST was 33% (Figure 2). Among those who discontinued IST, the median time from onset of late acute GVHD or NIH cGVHD to discontinuation of IST was 12 months. In a previous study, the median time to discontinuation of IST for patients with cGVHD after BMT or PBSCT was 23 months. Conclusions: Despite a highly HLA-mismatched donor source, the CI of cGVHD after CBT is comparable to that after conventional HLA-matched unrelated donor HCT previously reported from our center. Our results indicate that GVHD occurring after day 80 post CBT frequently manifests itself as acute GVHD predominantly involving the GI tract. More importantly, these preliminary results suggest that time to resolution of GVHD diagnosed after day 80 appears to be shorter after CBT compared to after BMT or PBSCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Biomarkers in acute graft-versus-host disease: new insights

2019 ◽  
Vol 10 ◽  
pp. 204062071989135 ◽  
Author(s):  
Hrishikesh K. Srinagesh ◽  
John E. Levine ◽  
James L.M. Ferrara
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
The United States ◽  
Response To Treatment ◽  
Gi Tract ◽  
Potential Measurement ◽  
Host Disease ◽  
Curative Therapy ◽  
Graft Versus Host

Hematopoietic cell transplantation (HCT) is a potentially curative therapy for hematologic malignancies that relies on the graft- versus-leukemia (GVL) effect to eradicate malignant cells. GVL is tightly linked to graft- versus-host disease (GVHD) however, in which donor T cells damage healthy host tissues. Acute GVHD occurs in nearly 50% of patients receiving HCT, and damages the skin, liver, and gastrointestinal (GI) tract. The organ stages are totaled in an overall grade (I–IV), and severe (grade III/IV) GVHD has a high mortality rate (50–70%). In the past decade, serum biomarkers have emerged as an additional potential measurement of acute GVHD severity. The discovery and validation of GVHD biomarkers is a principal objective of the Mount Sinai Acute GVHD International Consortium (MAGIC), a group of 25 HCT centers conducting GVHD research. MAGIC has validated an algorithm that combines two GI biomarkers (ST2 and REG3α) into a single value that estimates the probability of 6 month nonrelapse mortality (NRM) for individual patients, known as the MAGIC algorithm probability (MAP). The MAP reflects GI crypt damage and serves as a ‘liquid biopsy’ of the lower GI tract; it also predicts response to treatment and maximum GVHD severity and is now commercially available and widely used among scores of centers in clinical practice. The MAP is the focus of this review, with consideration of the categorization of types of biomarkers as defined by the United States National Institutes of Health (NIH) and Food and Drug Administration (FDA).

Interleukin-32, α1 Anti-Trypsin (AAT-1) and Graft-Versus-Host-Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 522-522
Author(s):  
A. Mario Q. Marcondes ◽  
Laura Tabellini ◽  
John A. Hansen ◽  
Charles A. Dinarello ◽  
H. Joachim Deeg
Keyword(s):  
Serine Protease ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Mrna Levels ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α

Abstract Abstract 522 Graft-versus-host disease (GVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). The role of various cell populations, cytokines and chemokines, present pre and post-transplantation, in the development of GVHD has been studied extensively.We investigated the potential role of Interleukin (IL)-32 in alloreactivity and GVHD. IL-32 is the protein product of the NK4 transcript first reported in IL-2 activated T lymphocytes and natural killer cells. IL-32 has pro-inflammatory and pro-apoptotic properties and induces expression of TNF-α in several cell targets. We used one-way mixed lymphocyte cultures (MLC) as a simple in vitro model of GVHD to determine IL-32 expression upon alloactivation. The α and γ isforms of (IL)-32 protein were 2-fold upregulated in allogeneic MLC compared to autologous controls (n=4, p=0.037). Concurrently, the concentrations of TNF-α, IL-6 and IL-8 in the allogeneic MLC supernatants were, as expected, upregulated significantly. This finding led us to evaluate IL-32 expression as a potential marker for GVHD after allogeneic HCT in 45 patients with either active acute GVHD or chronic GVHD, and 16 patients who did not show clinical evidence of GVHD. IL-32 mRNA levels in peripheral blood unsorted white blood cells, correlated with acute GVHD (RT-PCR values expressed as mean +/− SEM of the ratio of expression of IL-32/GUS-B = 1.01, p=0.011, vs control values IL-32/GUS-B = 0.23) but not with chronic GVHD, (IL-32/GUS-B = 0.26, p=0.16) (Figure 1). As the serine protease neutrophil proteinase 3 (PR3) has been shown to serve as activator of IL-32, and to process several inflammatory cytokines, including IL-32, TNF-α and IL-8, we postulated that the addition of the serine protease inhibitor α-1 anti-trypsin (AAT), would interfere with the processing of IL-32 by PR3, and as a result would lead to decreased proliferation of cells in MLC, and reduced cytokine production. To test this hypothesis, MLCs were treated with AAT at concentrations of 1–20 ug/ml and expression of IL-32 and PR3 were determined. In MLCs treated with AAT at the optimal concentration of 5 ug/ml, added to cultures on alternate days for a period of 7 days T lymphocyte proliferation was suppressed when compared to vehicle-treated MLC, (mean CPM=33.000 versus CPM=67.000; p=0.012). Concurrently there was a 2.5 fold decrease in IL-32 and PR3 protein levels (n=4, p=0.023). CONCLUSION: IL-32 is upregulated in patients with acute GVHD. Determination of IL-32 in patients with suspected GVHD may support the diagnosis and the decision to treat.AAT interferred with T cell activation and the release of cytokines, including IL-32, suggesting that administration of AAT may have therapeutic potential in patients with acute GVHD. Disclosures: No relevant conflicts of interest to declare.

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.

Both Tissue-Derived and Bone Marrow-Derived Host IL-17 Producing Cells Are Required for Preventing Acute Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2970-2970
Author(s):  
Rie Kuroda ◽  
Hideaki Maeba ◽  
Katsuaki Sato ◽  
Kazuhito Naka ◽  
Shintaro Mase ◽  
...  
Keyword(s):  
Protective Effect ◽  
Graft Versus Host Disease ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chimeric Mice ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Significant Difference ◽  
Acute Graft

Abstract Abstract 2970 Th17 is a newly identified T cell lineage, which secretes the proinflammatory cytokine IL-17. Th17 have been shown to play a crucial role in some immune-mediated diseases. We have reported that host-derived IL-17 has a protective effect against acute graft-versus-host disease (GVHD). In contrast, donor-derived IL-17 exacerbates chronic GVHD in rodent models. Briefly, in acute GVHD model, lethally irradiated IL-17 knockout (KO) recipient mice receiving allogeneic BM with low dose splenocytes developed more severe acute gut GVHD compared to wild type (WT) host mice and finally half of them died (p<0.05). To demonstrate the mechanisms of protective role of host derived IL-17 against acute GVHD in further detail, first we determined in vivo gut epithelial permeability by using FITC-dextran. No significant difference was observed between WT mice and IL-17KO mice, even in GVHD induced mice. Next, to exclude the possibility that alloreactivity of host IL-17KO derived mature dendritic cells (DCs) could be much more than that of WT DCs, mixed leukocyte reaction (MLR) was performed using stimulators from WT or IL-17KO mature DCs and responders from WT allogeneic splenocytes. There was no significant difference between WT mature DCs and IL-17KO mature DCs in thymidine uptake and percentage of responder cells producing IFN-γ or TNF-α. However, when DCs were cultured from BM cells with GM-CSF, co-stimulatory molecules such as CD80 and CD86 were expressed much stronger and from earlier time point on IL-17KO DCs compared with WT DCs. This suggested that DCs from IL-17KO tend to be activated much easier, resulting in much severe GVHD. In addition, when recombinant IL-17 was added into MLR mixture (Stimulator: Balb/c IL-17KO mature DCs, Responder: B6 IL-17KO splenocytes), proliferation was significantly decreased, demonstrating that IL-17 has inhibitory effect on alloreaciton. Next, much higher number of infiltrated monocyte/macrophage cluster was observed in spleen and gut in IL-17KO host mice. Residual host-typed peritoneal macrophages in IL-17KO host mice were highly activated with the expression of TNF-α, while activation of donor-typed macrophages was much less with the production of anti-inflammatory cytokine IL-10. Activated monocytes/macrophages in IL-17KO recipients might migrate into inflamed tissue much easier, partially because lack of IL-17 dose not block some macrophage chemotactic factors such as IP-10, RANTES. Finally to explore which host IL-17 producing cells are necessary for protection from acute GVHD, that is, BM-derived IL-17 producing cells or tissue derived IL-17 producing cells such as Paneth cells in the gut, [IL-17KO→WT], [WT→IL-17KO], [WT→WT], and [IL-17KO→IL-17KO] chimeric mice (Balb/c background) were created by reconstituting lethally irradiated WT or IL-17 KO Balb/c (H-2d) with BM cells from WT or IL-17 KO Balb/c mice. Four months later, chimeras were re-irradiated with 8Gy TBI and injected with WT C57BL/6(H-2b) BM plus low dose splenocytes to induce acute GVHD. Although [WT→WT] chimeric recipients were all alive, all [IL-17KO→IL-17KO] chimeric mice died of severe GVHD. In both [WT→IL-17KO] and [IL-17KO→WT] chimeras, half of them died with less GVHD compared to [IL-17KO→IL-17KO] recipients as shown below. This result indicated that as well as tissue derived IL-17, host BM derived IL-17 is necessary for protection from acute GVHD. In conclusion, host-derived IL-17 has a protective effect against acute GVHD due to in part by regulating APCs (monocytes/macrophages/DCs) activation and migration into GVHD target tissues. Disclosures: No relevant conflicts of interest to declare.

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 The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells

2011 ◽  
Vol 208 (2) ◽  
pp. 285-294 ◽  
Author(s):  
Shuichiro Takashima ◽  
Masanori Kadowaki ◽  
Kazutoshi Aoyama ◽  
Motoko Koyama ◽  
Takeshi Oshima ◽  
...  
Keyword(s):  
Stem Cells ◽  
Graft Versus Host Disease ◽  
Intestinal Epithelium ◽  
Critical Role ◽  
Intestinal Stem Cells ◽  
Allogeneic Bone ◽  
Gi Tract ◽  
Host Disease ◽  
Graft Versus Host ◽  
Allogeneic Bmt

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.

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