scholarly journals Ex vivo detection of adenovirus specific CD4+ T-cell responses to HLA-DR-epitopes of the Hexon protein show a contracted specificity of THELPER cells following stem cell transplantation

Virology ◽  
2010 ◽  
Vol 397 (2) ◽  
pp. 277-284 ◽  
Author(s):  
Celine Serangeli ◽  
Oliver Bicanic ◽  
Michael H. Scheible ◽  
Dorothee Wernet ◽  
Peter Lang ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Hexon Protein ◽  
Hla Dr

CTL Responses Against Tumor Associated Antigens Are Part of the Graft Versus Leukemia-Effect and Protect from Relapse after Allogeneic Hematopoetic Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3231-3231
Author(s):  
Markus Kapp ◽  
Stefan Stevanovic ◽  
Kerstin Fick ◽  
Juergen Loeffler ◽  
Sen Mui Tan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Proteinase 3 ◽  
Post Transplantation ◽  
Cell Responses

Abstract The Graft-versus-Leukemia (GVL) effect following allogeneic hematopoetic stem cell transplantation (HSCT) is one of the most prominent examples showing the ability of the immune system to eliminate malignant diseases. This effect was a strictly clinically described phenomenon, but in the last years T-cell responses against tumor-associated antigens (TAA) could partly be set in correlation with clinical benefit. Previously, TAA such as WT1 and proteinase-3 have been proposed as the targets for T-cells to establish a GVL effect. Now, we examined in addition other TAA (MUC1 and HM1.24) as possible T-cell targets of GVL related immune responses. We have defined new peptide epitopes from the MUC1 and HM1.24 antigens by the reverse immunology approach to increase the number of patients who can be screened and to expand the repertoire of immunologic monitoring as well as therapeutic approaches. A total of 25 patients after allogeneic stem cell transplantation have been screened and we are able to detect T-cell responses to both the MUC1 and HM1.24 antigens on top of the WT1 and the proteinase-3 antigen. Interestingly, we could detect a significant relationship between relapse and the absence of a T-cell response to TAA: Only 1/10 patients (10%) with TAA-specific CTL relapsed in contrast to 8/15 patients (53.3%) without TAA-specific CTL responses (p < 0.05). Furthermore, we demonstrated MUC1 peptides presented by HLA A*6801, B*0702 and B*4402 to be specifically recognized by CD3+/CD8+ T-cells. In conclusion, CD8+ T-cell responses directed to TAA might contribute to the GVL effect and are not limited to WT1 and proteinase-3. These observations clearly highlight both the importance and the potential of immunotherapeutic approaches in allogeneic stem cell recipients. Figure 1: New defined HLA class I epitopes predicted by computer analysis are recognized by specific CTL in patients post allogeneic HSCT. IFN-γ staining of PBMC from, patient No. 17 (AML, CR), 672 days post transplantation (A), patient No. 8 (AML, CR), 1035 days post transplantation (B) Cells were stimulated with 10μg/ml of the indicated peptides. Gates were set on lymphocytes by forward/side scattering (R1) and on CD3+/CD8+ cells (R2). Percentage numbers show peptide-specific CD3+/CD8+ T-cells from all CD3+/CD8+ T-cells. Figure 1:. New defined HLA class I epitopes predicted by computer analysis are recognized by specific CTL in patients post allogeneic HSCT. . / IFN-γ staining of PBMC from, patient No. 17 (AML, CR), 672 days post transplantation (A), patient No. 8 (AML, CR), 1035 days post transplantation (B) Cells were stimulated with 10μg/ml of the indicated peptides. Gates were set on lymphocytes by forward/side scattering (R1) and on CD3+/CD8+ cells (R2). Percentage numbers show peptide-specific CD3+/CD8+ T-cells from all CD3+/CD8+ T-cells.

Detection of Th1 Driven T-Cell Responses in Peripheral Could Guide Individualized Immunosuppression and Risk of Viral Reactivation Under GvHD Prophylaxis Following Allogeneic Stem Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3047-3047
Author(s):  
Judith Feucht ◽  
Kathrin Opherk ◽  
Cornelia Neinhaus ◽  
Simone Kayser ◽  
Wolfgang A. Bethge ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
T Cell Responses ◽  
Cell Responses ◽  
Cell Immunity

Abstract Abstract 3047 Allogeneic stem cell transplantation (SCT) can expose patients to a transient but marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. The control of these infections will ultimately depend on the restoration of adequate T-cell immunity. Most viral infections after SCT are caused by endogenous reactivation of persistent pathogens such as cytomegalovirus (CMV), adenovirus (ADV) and Epstein-Barr-virus (EBV). Risk of viral complications is even higher under GvHD treatment or prophylaxis like calcineurin inhibitors and steroids. Post transplant often the immunosuppression needs to be reduced to improve viral complications with the risk of GvHD. The virus-specific T-cell responses in peripheral blood have been shown to be a good marker of immunological protection, but has not been used for clinical decision making and the guidance of drug plasma levels. Therefore, we performed a prospective clinical trial in 33 adult and pediatric patients after allogeneic stem cell transplantation receiving pharmacologic immunosuppression with steroids, Cyclosporin A, Tacrolimus, Everolimus or Mycophenolate. Median Age was 16 years. T-cell responses were analyzed ex vivo against Cytomegalovirus (pp65), Adenovirus (hexon antigen) and Epstein-Barr Virus (EBNA, LMP) using intracellular cytokine staining. In addition in vitro analysis of the proliferation responses using CFSE were performed. Responses were compared to healthy donors. The T-cell responses in vitro under low, high and supraphysiologic plasma concentrations of the respective drugs were investigated. Under the direct influence of steroids, activated, virus-specific T-cells underwent apoptosis. Among the Calcineurin inhibitors, Tacrolimus had the strongest inhibition on virus-specific T-cell immunity, followed by Cyclosporin A. But, under low therapeutic levels, Virus speciffic T-cell responses have been able to develop in PBMCs. Mycophenolate had only in high concentrations a strong effect on the T-cell response against viral pathogens. Relevant differences in the frequency of virus-specific T-cells secreting IFN-g could be detected within the CD4 compartment in correlation to the level of immunosuppression. In conclusion we could show that detection of virus-specific T-cells could be used to guide the level of immunosuppression in case of viral complications after allogeneic stem cell transplantation, since emergence of in vivo T-cell responses was closely associated with a clearance or reduction of the viral load. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation

Blood ◽  
2012 ◽  
Vol 120 (14) ◽  
pp. 2899-2908 ◽  
Author(s):  
Todd V. Brennan ◽  
Liwen Lin ◽  
Xiaopei Huang ◽  
Diana M. Cardona ◽  
Zhiguo Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Heparan Sulfate ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
T Cell Responses ◽  
Hematopoietic Stem ◽  
Cell Responses ◽  
Alloreactive T Cell

Abstract Graft-versus-host disease (GVHD) remains the most common cause of nonrelapse-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosuppression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recurrence. In this study, we showed that heparan sulfate (HS), an extracellular matrix component, can activate Toll-like receptor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell maturation and alloreactive T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor α1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and correlated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD.

PR1-Specific T Cell Responses in the First Months Following T-Cell Depleted Allogeneic Stem Cell Transplantation Occur in Both Myeloid and Non-Myeloid Malignancies but Are Only Associated with a GVL Effect in Myeloid Leukemias.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5195-5195
Author(s):  
Katayoun Rezvani ◽  
Yong Agnes ◽  
Rhoda B. Eniafe ◽  
Stephan Mielke ◽  
Bipin N. Savani ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Self Antigens

Abstract The immune milieu in the first few months post-stem cell transplantation (SCT) is favorable for graft-versus-leukemia (GVL) responses. A homeostatic drive caused by lymphopenia stimulates expansions of transplanted donor T-cells responding to diverse antigenic stimuli in the recipient. Human leukemia antigens such as proteinase 3 (PR3) and elastase (ELA2) are self-antigens which induce low but detectable frequencies of autoreactive T cells in normal individuals. PR1, an HLA-A*0201 restricted peptide shared by PR3 and ELA2, is expressed in normal neutrophils and overexpressed in myeloid (but not lymphoid) leukemias. T-cell responses against PR1 have been linked to GVL. We studied patients early post SCT to look for early induction of T cell responses to PR1, and correlate them with ELA2 and PR3 expression and GVL effects. Using PR1/HLA-A*0201 tetramers and flow cytometry for intracellular IFN-gamma, we analyzed PBMC for CD8+ T-cell responses against PR1 on days 30, 60, 90 and 120 following a T-depleted SCT in 28 patients (13 CML, 10 ALL, 5 solid tumor). Ten patients with CML, 6 with ALL and 3 with solid tumors had detectable PR1 responses post-SCT. PR1 specific CD8+ T cells had a predominantly effector-memory phenotype (CD45RO+CD27−CD57+). PR3 and ELA2 gene expression in these samples was assessed by RQ-PCR and found to be significantly correlated (P < 0.001). There was a strong association between the expression of PR3 and ELA2 and the emergence of PR1 specific CD8+ T-cell responses. Conversely, reduction or disappearance of PR3 and ELA-2 expression from blood coincided with reduction or disappearance of PR1 specific CD8+ T-cell responses (P <0.001) (as depicted below). The in-vivo anti-leukemia effect of the PR1 response was assessed in CML patients by BCR-ABL transcript numbers at day 90 post-SCT. Eight of ten patients with significant PR1 responses post-SCT were BCR-ABL negative at day 90 compared to 1 of 3 without PR1 responses (P <0.001). This GVL association was restricted to CML patients: in ALL using WT1 gene expression as a measure of minimal residual disease (MRD) 2 of 5 patients with PR1 responses and 3 of 5 patients without were MRD positive on day 90 post-SCT (P =0.36). Since PR1 responses were not restricted to CML and because these transplant approaches usually induce 100% donor myeloid chimerism by day 30 post-SCT, the recovering donor marrow is the likely antigenic source of PR3 and ELA2 driving the PR1 response. Our findings suggest that the post-SCT milieu is favorable for exaggerating weak autoimmune responses to self antigens such as PR1 causing antigen-specific T-cell proliferation. GVL effects may follow if the self antigen is expressed on the leukemia as occurs in CML. These results suggest that vaccination in conjunction with induction of T cell homeostatic proliferation is likely to enhance the anti-leukemia response and effectiveness of a transplant procedure. Figure Figure

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