scholarly journals Peripheral Blood Expansion of CD38 Bright CD8+ Effector Memory T-Cells Predicts Acute Graft Versus Host Disease with a Diagnostic Accuracy of 87%

2015 ◽  
Vol 21 (2) ◽  
pp. S99-S101
Author(s):  
Pooja Khandelwal ◽  
Adam Lane ◽  
Erika Owsley ◽  
Vijaya Chaturvedi ◽  
Michael B. Jordan ◽  
...  
2015 ◽  
Vol 21 (7) ◽  
pp. 1215-1222 ◽  
Author(s):  
Pooja Khandelwal ◽  
Adam Lane ◽  
Vijaya Chaturvedi ◽  
Erika Owsley ◽  
Stella M. Davies ◽  
...  

2012 ◽  
Vol 18 (10) ◽  
pp. 1488-1499 ◽  
Author(s):  
Ping Zhang ◽  
Jieying Wu ◽  
Divino Deoliveira ◽  
Nelson J. Chao ◽  
Benny J. Chen

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4652-4658 ◽  
Author(s):  
Thomas V. Tittle ◽  
Andrew D. Weinberg ◽  
Cara N. Steinkeler ◽  
Richard T. Maziarz

Abstract The OX-40 molecule is expressed on the surface of recently activated T lymphocytes. The presence of OX-40 on CD4+ T cells was analyzed in a rat haplo-identical (parental → F1) bone marrow transplant model of acute graft-versus-host disease (aGVHD). Increased numbers of activated CD4+ T cells that expressed the OX-40 antigen were detected in peripheral blood soon after transplantation before the earliest sign of disease. The peak of OX-40 expression occurred 12 days posttransplantation with a range of 18% to 36% of circulating T cells and remained 10-fold above background, never returning to baseline. A slight increase in OX-40 expression (range, 1% to 6%) was also detected on peripheral blood lymphocytes from control syngeneic F1 → F1 recipients. OX-40+ T cells were isolated from spleen, skin, lymph node, and liver tissue of rats undergoing aGVHD, but not in syngeneic transplants. OX-40+ T cells isolated from these tissues were of donor origin and were shown to be allo-reactive. These data raise the possibility of using the OX-40 antibody to detect and deplete selectively the T cells that cause aGVHD.


Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5242-5251 ◽  
Author(s):  
Britt E. Anderson ◽  
Patricia A. Taylor ◽  
Jennifer M. McNiff ◽  
Dhanpat Jain ◽  
Anthony J. Demetris ◽  
...  

Abstract Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation. Effector memory T cells (TEM) do not cause GVHD but engraft and mount immune responses, including graft-versus-tumor effects. One potential explanation for the inability of TEM to cause GVHD is that TEM lack CD62L and CCR7, which are instrumental in directing naive T cells (TN) to lymph nodes (LN) and Peyer patches (PP), putative sites of GVHD initiation. Thus TEM should be relatively excluded from LN and PP, possibly explaining their inability to cause GVHD. We tested this hypothesis using T cells deficient in CD62L or CCR7, transplant recipients lacking PNAd ligands for CD62L, and recipients without LN and PP or LN, PP, and spleen. Surprisingly, CD62L and CCR7 were not required for TN-mediated GVHD. Moreover, in multiple strain pairings, GVHD developed in recipients that lacked LN and PP. Mild GVHD could even be induced in mice lacking all major secondary lymphoid tissues (SLT). Conversely, enforced constitutive expression of CD62L on TEM did not endow them with the ability to cause GVHD. Taken together, these data argue against the hypothesis that TEM fail to induce GVHD because of inefficient trafficking to LN and PP.


Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 3115-3123 ◽  
Author(s):  
Benny J. Chen ◽  
Divino Deoliveira ◽  
Xiuyu Cui ◽  
Ngocdiep T. Le ◽  
Jessica Son ◽  
...  

Abstract Several groups, including our own, have independently demonstrated that effector memory T cells from non–alloantigen-primed donors do not cause graft-versus-host disease (GVHD). In the current study, we further investigated whether this approach could be extended to all memory T cells, and we studied the underlying mechanisms. Neither total memory T cells nor purified central memory T cells were able to induce GVHD. Memory T cells were at least 3-log less potent than bulk T cells in mediating GVHD. As expected, memory T cells failed to elicit cytotoxicity and proliferated poorly against alloantigens in standard 5-day mixed-lymphocyte cultures. However, the proliferative responses of memory T cells were more comparable with those of bulk and naive T cells when the culture time was shortened. Moreover, the frequencies of IL-2–secreting cells measured by 42-hour enzyme-linked immunosorbent spot (ELISPOT) assay were similar among naive, memory, and bulk T cells. These data indicated that memory T cells are able to respond to alloantigens initially but fail to develop to full potential. The abortive immune response, which was mediated by non–alloantigen-specific memory T cells in response to alloantigens, may explain why memory T cells from unprimed and non–alloantigen-primed donors could not induce GVHD.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 232-232
Author(s):  
Ping Zhang ◽  
Jieying Wu ◽  
Divino Deoliveria ◽  
Nelson J. Chao ◽  
Benny J. Chen

Abstract Abstract 232 Several different groups have independently demonstrated that non-allospecific effector memory T cells do not induce graft-versus-host disease (GVHD). Limited data are available regarding the ability of allospecific effector memory T cells to induce GVHD. We first studied this question in the C57BL/6 into BALB/c model. Similar to the data previously published by other groups, purified CD62L- effector memory T cells isolated from donors, who were primed with the host antigens 8 weeks earlier, had decreased ability to induce acute GVHD compared with unseparated and CD62L+ T cells. Similar results were observed when the parous female mice, who were sensitized to the host antigens during pregnancy, were used as memory T cell donors. In order to study this question more definitely and to understand the mechanisms underlying these surprising observations, we further studied the ability of allospecific effector memory T cells to induce GVHD using a novel GVHD model mediated by transgenic TEa T cells. All TEa T cells are CD4+ and recognize the same peptide in the context of I-Ab. This peptide corresponds to positions 52-68 from the alpha-chain of I-E class II molecules and is expressed in all antigen presenting cells from H-2b/I-E+ strains such as CB6F1 mice. To generate memory T cells, naïve TEa cells were first parked in Rag1−/− mice and then immunized with irradiated CB6F1 spleen cells. More than eight weeks later, ∼98% of TEa cells obtained a memory phenotype (CD44high, CD45RB-.CD127+,CD11a bright, FasL bright, Ki67-, CD28-, KLRG-). Of them, about 93% were CD62L-CD44high effector memory T cells and 7% were CD62L+CD44high central memory T cells. These Rag1−/− mice that contained memory phenotype TEa cells rejected CB6F1 skin grafts much faster than naïve TEa mice did (median survival time: 6.5 vs. 13 days, P=0.01), suggesting that the memory phenotype T cells contained in these mice are functional. Moreover, CD62L-CD44high TEa cells purified from these mice mediated faster and stronger in vitro proliferative responses against alloantigens than naïve TEa cells did, further demonstrating that they are true functional effector memory T cells. We next tested the ability of these effector memory TEa cells to induce GVHD. Effector memory TEa cells were obtained after depletion of CD62L+ cells using magnetic beads and the purity was more than 99%. Transplantation of 1′105 TEa naïve T cells together with 1′107 T cell depleted bone marrow cells into lethally irradiated CB6F1 recipients induced lethal GVHD in all recipients and all animals in this group died within 35 days after transplantation. In contrast, none of the effector memory TEa cell recipients developed GVHD and all of them survived more than 100 days post transplantation (P<0.01, compared with naïve T cell control). To understand the mechanisms underlying these observations, we studied the kinetics of TEa proliferative responses upon challenge with alloantigens. The data indicated that effector memory TEa cells reached the peak responses faster than naïve TEa cells did. CFSE tracking experiment further confirmed this observation. Simultaneous staining with anti-Anexin V antibody and 7-AAD demonstrated that effector memory TEa cells undergone apoptosis and died faster than naïve T cells did. In conclusion, these data underscore the fundamental difference of alloresponses mediated by antigen-specific effector memory T cells in graft rejection and GVHD settings. The TEa transgenic T cell skin graft and GVHD models would allow further understanding of the unique alloresponses mediated by allospecific memory T lymphocytes in GVHD. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5721-5721
Author(s):  
Pauline Varlet ◽  
Tamim Alsuliman ◽  
Jacques Trauet ◽  
Julie Demaret ◽  
Myriam Labalette ◽  
...  

Abstract Introduction Historically the administration of post-transplant high-dose Cyclophosphamide (PTCy) has led to haplo-HCT re-innovation. Although PTCy has a positive impact towards reducing severe acute graft-versus-host disease (aGVHD), this drug has serious adverse side effects and makes haploidentical-HCT more difficult in some patients-particularly in older patients and/or those presenting other comorbidities. Considering our previous published experience in the effect of graft lymphocyte composition, this work aims to explore the impact of infused T cell subsets on Overall Survival (OS), Event Free Survival (EFS) and acute GVHD in a retrospective cohort receiving allogeneic haplo-HCT. Methods This study retrospectively analyzed 29 adult patients who underwent first allogeneic haplo-HCT for hematologic malignancies at Lille University Hospital (CHRU Lille, France). Graft samples were analyzed by flow cytometry, and CD4 and CD8 T cell subsets were defined as follows: TN=naïve T cells; , TCM=central memory T cells; TEM=effector memory T cells; TTD =terminally differentiated T cells. Results The median follow-up of patients was 11 months (0.4-44.3). The cohort median recipient age was 59 years old. Cumulative incidences of grade 2 to 4 aGVHD were 31%. The rate of grade 3 to 4 severe GVHD was 17%. Eleven patients died with 14% of deaths due to non-relapse mortality. We found a correlation between high percentage of donor-derived CD4+ CCR7+ T cells (>69.2% for CD4+ T cells-the median value in our study) and aGVHD (p=0.028) without any impact on OS and EFS (Table 1). In multivariate analysis, only high proportions of donor CD4+ CCR7+ T cells correlated significantly with aGVHD (HR=0.203, 95% CI [0,042-0,980], p=0,047) without any impact on OS and EFS (Figure 1). Conclusion Naïve and central memory T cells expressing CCR7 exhibit higher alloreactivity potential than CCR7- T cells. In this study, even with PTCy administration, we observed that a high percentage of donor-derived CD4+ CCR7+ T cells can be considered as a predictive indicator of grade II-IV aGVHD post Haplo-HCT. Thus, selective depletion of CD4+ CCR7+ T cells might be enough to prevent aGVHD in haplo-HCT, enabling the use of low doses of PTCy in order to reduce post haplo-HCT complications. Disclosures No relevant conflicts of interest to declare.


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