scholarly journals Differential Effect of MyD88 Signal in Donor T Cells on Graft-versus-Leukemia Effect and Graft-versus-Host Disease after Experimental Allogeneic Stem Cell Transplantation

2015 ◽  
Vol 38 (11) ◽  
pp. 966-974 ◽  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Differential Effect ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Donor T Cells ◽  
Graft Versus Leukemia Effect

Attenuated Acute Graft-Versus-Host Disease Following Allogeneic Stem Cell Transplantation In the Absence of RORγt.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3742-3742
Author(s):  
LeShara M Fulton ◽  
Michael J Carlson ◽  
James Coghill ◽  
Michelle L. West ◽  
Angela Panoskaltisis-Mortari ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Abstract 3742 CD4+ T helper (Th) cells play a critical role in the development of Graft-versus-Host Disease (GvHD). The relative contributions of particular Th subsets to GVHD pathogenesis, however, are incompletely understood. In order to clarify the contribution of the Th17 subset to GVHD induction, we made use of mice knocked out at the RORgt locus (RORgt−/−), a transcription factor crucial for Th17 polarization. Methods: Haplotype matched and complete MHC mismatched murine HSCT models were used. For the haploidentical model C57BL/6 (H-2b, B6) mice served as donors while C57BL/6 × DBA2 F1 (H-2bxd, B6D2) mice functioned as recipients. Effector T cells (Teffs) were isolated from the spleens of wild type (WT) B6 and RORgt knockout mice backcrossed 7–8 generations onto a B6 background. B6D2 mice were lethally irradiated with 900 rads on day -1 and injected intravenously with 4 × 106 Teffs from WT or RORgt−/− mice supplemented with 3 × 106 WT T cell depleted bone marrow cells (TCD BM) on day 0. For the completely MHC mismatched model, BALB/c mice (H-2d) were lethally irradiated with 800 rads on day -1 and administered 5 × 105 WT or RORgt−/− Teffs supplemented with 5 × 106 B6 TCD BM on day 0. Results: B6D2 mice that received RORgt−/− Teffs displayed significantly attenuated GvHD, recovering from weight loss by day +31 and demonstrating 100% survival on day +60. Conversely, mice that received WT Teffs showed intense disease progression with 100% mortality by day +31 (Figure A, p<0.0001 for survival comparison between WT and RORgt−/− recipients using Fisher's exact test). Similar results were seen using the completely MHC mismatched model, with superior overall survival noted in those animals receiving RORgt −/− Teffs (put in p value here). Recipients of RORgt −/− T cells demonstrated statistically significant decreased TNF in serum compared to WT recipients (Figure B, p=0.001 comparing WT and RORgt−/− recipients using student's t test). Interestingly, despite the decreased severity of GvHD, serum concentrations of IFN-g were increased in recipients transplanted with RORgt −/− T cells. Chimerism studies post-transplant revealed complete donor reconstitution in recipients of both RORgt−/− and WT Teffs. Donor Teffs isolated from recipient livers post-transplant consistently demonstrated an activated phenotype, with low L selectin and high CD25 expression. Conclusions: T cell expression of the Th17 transcription factor, RORgt, is critical for the development of lethal GvHD following allogeneic stem cell transplantation in both the haploidentical and MHC complete mismatch models. GvHD attenuation in the absence of RORgt is not the result of an inability for donor T cells to undergo activation or to engraft in vivo. Interestingly, the absence of RORgt from donor T cells led to enhanced IFN-g in serum. Thus, in vivo, the Th17 pathway is critical for the induction of GvHD. Disclosures: No relevant conflicts of interest to declare.

The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of the FOXP3 Gene Influences Graft Versus Host Disease without Affecting Graft Versus Leukemia Effect After Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3051-3051
Author(s):  
Victor Noriega ◽  
Carolina Martinez-Laperche ◽  
Leyre Bento ◽  
Noemi Sanchez-Hernandez ◽  
Milagros Gonzalez-Rivera ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Foxp3 Gene ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Graft Versus Leukemia Effect

Abstract Abstract 3051 INTRODUCTION The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+, Tregs) which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation (allo-SCT), Tregs are known to mitigate graft versus host disease (GVHD) while maintaining a graft versus leukemia effect (GVL). Allele (GT)15 for the functional (GT)n polymorphism in the promoter/enhancer of the FOXP3 gene is associated with a higher expression of FOXP3 and production of a greater amount of Tregs. However, its impact in the allo-SCT setting has not been analyzed. OBJECTIVE To analyze the impact of the (GT)n polymorphism in the promoter/enhancer of the FOXP3 gene on the development of complications and ultimately on the success of conventional HLA-identical allo-SCT. MATERIALS AND METHODS The study includes 33 patients with hematological malignancies, treated with myeloablative HLA-identical peripheral blood allo-SCT (Table 1). Diagnosis, classification and grading of GVHD were made by clinical criteria and confirmed when necessary by pathological examination of histological samples from gut, skin, liver or lung, according to international consensus criteria. Donor and recipient genomic DNA was purified from EDTA anticoagulated peripheral blood before allo-SCT and using QIAamp Blood DNA extraction kit (Qiagen). Genotyping of the (GT)n microsatellite polymorphism in the FOXP3 gene was performed by a fluorescence-based short tandem repeat-polymerase chain reaction (STR-PCR) method (GeneAmp 7900; Applied Biosystems) and sized by capillary electrophoresis (POP7 - ABI PRISM 3130 xL Genetic Analyzer; Applied Biosystems) followed by fragment analysis (GeneMapper 4.0 Software; Applied Biosystems) as previously described [Bassuny WM, et al. Immunogenetics. 2003;55 :149–56]. RESULTS The median follow-up time for the cohort was 34 months (range 9.5–110). Allelic frequencies observed were similar to those previously reported (50.5% (GT)15, 41% (GT)16 and 7% (GT)17; no (GT)14 or (GT)18 alleles were found). Patients transplanted from donors harboring allele (GT)15 showed a lower incidence of grades II-IV acute GVHD (29% vs 67%; p =0.049). These patients also showed a trend to a lower incidence of severe (grades III-IV) GVHD (12% vs 33%; p =0.167) as well as chronic GVHD (75% vs 100%; p =0.143; Table 1, Figure 1). No statistically differences were found between patients transplanted from (GT)15 and non-(GT)15 donors in terms of relapse rate (38% vs 33%; p =0.825; Table 1) or cumulative incidence of relapse (CIR at 2 years 35.3% vs 37.5%, Figure 2). Finally, survival analysis did not show statistically significant differences between the two groups of patients in terms of median event (relapse) free survival (EFS, 15.6 months vs 4.5 months, p =0.686) or overall survival (OS, 29 months vs not reached, p =0.610). CONCLUSIONS Tregs are known to modulate the allotolerance-alloreactivity balance between donor and recipient in the allo-SCT setting, mitigating GVHD while preserving the anti-tumor effect (GVL) of the donor graft. In the present study, the presence of allele (GT)15 in the donor, which promotes a higher expression of FOXP3 and greater amount of Tregs, affected allo-SCT outcome by decreasing grades II-IV acute GVHD and chronic GVHD, without affecting GVL (no differences in CIR and OS). Analysis of this polymorphism can help in appropriate donor selection and, more importantly, drive a tailored management of patients submitted to allo-SCT. Disclosures: No relevant conflicts of interest to declare.

Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation

Blood ◽  
2013 ◽  
Vol 121 (18) ◽  
pp. 3745-3758 ◽  
Author(s):  
Emily Blyth ◽  
Leighton Clancy ◽  
Renee Simms ◽  
Chun K. K. Ma ◽  
Jane Burgess ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Organ Damage ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points

Key Points Infusion of CMV-specific T cells early posttransplant does not increase acute or chronic graft-versus-host disease. CMV-specific T cells early posttransplant reduce the need for pharmacotherapy without increased rates of CMV-related organ damage.

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