Lenalidomide Is Highly Effective in Patients with Relapsed Multiple Myeloma Following Allogeneic Stem Cell Transplantation and Increases the Frequency of CD4+FOXP3+ T Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2722-2722
Author(s):  
Monique C. Minnema ◽  
Michael van der Veer ◽  
Tineke Aarts ◽  
Maarten Emmelot ◽  
Tuna Mutis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Response Rate ◽  
Cell Populations ◽  
Ifn Γ ◽  
Grade 3

Abstract Lenalidomide has demonstrated significant clinical activity in patients with newly diagnosed and relapsed multiple myeloma (MM). Its actions are partly mediated by stimulation of cellular host anti–MM immunity. Given these potent immunomodulatory effects, we analysed whether lenalidomide could enhance graft versus tumour or graft versus Host (GvH) reactions and analysed the efficacy and toxicity of lenalidomide after allogeneic stem cell transplantation (allo-SCT). Lenalidomide 25 mg/day was given for 21 days followed by 1 week rest for a maximum of 6 cycles to 11 end-stage patients with relapsed MM following allo–SCT. Seven patients were refractory to their last treatment. From 5 patients peripheral blood was collected before, during and after lenalidomide treatment for analysis of CD4+, CD8+ T–cells, plasmacytoid and myeloid dendritic cells, regulatory T cells and NK cell populations by FACS. Also the percentage of CD4+FOXP3+ cells and IL–10 and IFN–γ producing CD4+ and CD8+ T cells were analysed by FACS. Dexamethasone 40 mg/day was added on day 1–4 and 15–18 at start of treatment in patients 2 and 5, or after 2 cycles in patients 3, 9 and 10. A high response rate was observed in these patients. Four patients developed complete (CR) or very good partial remissions (VGPR) after 1–5 treatment cycles. Three patients developed acute GvH disease (GvHD), grade 2–4. In 1 patient long lasting chronic GvHD was diminished, in another resolved. Other toxicities beyond CTC AE grade 1 were 1 patient with grade 3 diarrhoea, 1 with grade 3 muscular pain and 1 patient with grade 4 pulmonary embolism. There were 2 patients with leukocytopenia grade 3 and 4 and 2 patients with thrombocytopenia grade 2 and 3. Comprehensive immunomonitoring of 2 poor responders with stable disease (SD) or minimal response (MR) and 3 responders revealed generally no significant changes in dendritic cell populations, CD4+ and CD8+ T cells, CD56dim, CD56high and invariant NK cells. In 4/5 patients lenalidomide increased the frequency of IFN–γ producing CD4+ and CD8+ T cells. In 3/5 patients there was a decrease in the percentage of IL–10 producing CD8+ and CD4+ T cells. Remarkably, in 4/5 patients lenalidomide treatment induced a strong increase in the frequency of CD4+FOXP3+ T cells, which are considered to represent natural regulatory T cells (Tregs). In conclusion, our results reveal for the first time the potent effects with limited toxicity of lenalidomide in the allo–SCT setting with a response rate in 9 of 11 patients. In 4 of 5 patients tested we demonstrated an increase in Tregs and IFN–γ producing T cells, indicating that the action of lenalidomide is associated with immunomodulatory events involving both effector and Treg cell populations. Nr Age/Sex Refractory to last treatment Max Response/nr cycli GvHD FOXP3♣ IFNγ♣ IL-10♣ 1 62/F yes PR/2 BOS↓ nd nd nd 2 67/F yes PR/2 no nd nd nd 3 44/M yes PR/2 no 2,5↑ 3↑ 2↓ 4 62/F yes CR/4 no 0,3↓ 0 0 5 49/M yes PR/1 BOS = nd nd nd 6 64/M no PR/2 no nd nd nd 7 64/M no CR/4 acute gr 2, chronic↓ nd nd nd 8 56/F* yes VGPR/1 acute gr 4 5↑ 5↑ 2↑ 9 43/M no SD/2 no 5↑ 2↑ 2↓ 10 66/M yes VGPR/5 no nd nd nd 11 63/M† yes MR/1 acute gr 3 6↑ 2↑ 3↓

scholarly journals B and T Lymphocyte Attenuator Mediates Inhibition of Tumor-Reactive CD8+ T Cells in Patients After Allogeneic Stem Cell Transplantation

2012 ◽  
Vol 189 (1) ◽  
pp. 39-49 ◽  
Author(s):  
Willemijn Hobo ◽  
Wieger J. Norde ◽  
Nicolaas Schaap ◽  
Hanny Fredrix ◽  
Frans Maas ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation

scholarly journals T-cell receptor-α repertoire of CD8+ T cells following allogeneic stem cell transplantation using next-generation sequencing

Haematologica ◽  
2018 ◽  
Vol 104 (3) ◽  
pp. 622-631 ◽  
Author(s):  
Cornelia S. Link-Rachner ◽  
Anne Eugster ◽  
Elke Rücker-Braun ◽  
Falk Heidenreich ◽  
Uta Oelschlägel ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Next Generation Sequencing ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Cell Receptor ◽  
Generation Sequencing

Automated Generation of Antigen-Specific T Cells for Adoptive T Cell Therapy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1177-1177
Author(s):  
Melanie Fahrendorff ◽  
Nanette von Oppen ◽  
Georg Rauser ◽  
Mario Assenmacher ◽  
Juergen Schmitz ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Closed System ◽  
Isolated Cells ◽  
Ifn Gamma ◽  
Cell Processing

Abstract Abstract 1177 The adoptive transfer of antigen-specific T cells can be a powerful tool for immunotherapy of malignant diseases or infectious complications after allogeneic stem cell transplantation (Riddell et al., 1992; Heslop et al. 2010). Human adenovirus (AdV), Epstein-Barr virus (EBV) or cytomegalovirus (HCMV) infections are frequent and often life-threatening complications post allogeneic stem cell transplantation. To reduce the time required to isolate antigen-specific T cells for adoptive transfer we have developed a method to isolate IFN-gamma-secreting CD4+ as well as CD8+ T cells after antigen-specific restimulation, the Cytokine Capture System IFN-gamma (CCS). Several preclinical studies demonstrate the efficient enrichment of functional CD4+ and CD8+ T cells specific for HCMV (Rauser et al., 2004), EBV (Hammer et al., 2007) or AdV (Feuchtinger et al. 2008) using the CCS. First clinical data of adoptively transferred HCMV-, EBV- or AdV-specific T cells into patients post allogeneic stem cell transplantation are very encouraging (Feuchtinger et al., 2010; Moosmann et al., 2010; Feuchtinger et al., 2006) with low T cell doses infused varying from 1–97×10e3 cells/kg. We have now developed a cell processing device for the automation of the CCS procedure. Antigen-specific stimulation, labeling with the CCS reagents, washing steps, cytokine capture, magnetic enrichment and potentially expansion of the isolated cells are performed fully automated in a closed system. At the beginning of the procedure all components including the cellular starting product, antigen(s), reagents, buffer, and media are connected to a sterile single-use closed system processing set in the device. Due to usage of sterile filters and sterile docking the whole process runs under sterile conditions. The cellular end product can be obtained in the medium/buffer of choice, with the desired cell concentration and volume. The cellular starting product can be leukapheresis or bone marrow and the yield of antigen-specific T cells depends on the frequency of IFN-gamma producing cells. When starting with 1×10e9 cells 1–20×10e5 HCMV-specific T cells could be isolated. Cell processing is possible overnight and the isolated cells might be used directly after enrichment or after a phase of in vitro expansion. Using this cell processing device, IFN-gamma secreting HCMV-specific T cells were enriched to the same purity (>80% IFN-gamma secreting CD4+ and CD8+ T cells) as with the semi-automated procedure. Cell loss during the procedure is markedly reduced, leading to an increased yield of IFN-gamma positive cells. An improved viability was observed resulting in better expansion rates. In conclusion, the automation in a closed system enables the fast and robust generation of antigen-specific T cells for adoptive therapy and will reduce clean room requirements. Disclosures: Fahrendorff: Miltenyi Biotec GmbH: Employment. von Oppen:Miltenyi Biotec GmbH: Employment. Rauser:Miltenyi Biotec GmbH: Employment. Assenmacher:Miltenyi Biotec GmbH: Employment. Schmitz:Miltenyi Biotec GmbH: Employment. Biehl:Miltenyi Biotec GmbH: Employment. Miltenyi:Miltenyi Biotec GmbH: Membership on an entity's Board of Directors or advisory committees.

Functional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation

Blood ◽  
2003 ◽  
Vol 102 (8) ◽  
pp. 2892-2900 ◽  
Author(s):  
Katayoun Rezvani ◽  
Matthias Grube ◽  
Jason M. Brenchley ◽  
Giuseppe Sconocchia ◽  
Hiroshi Fujiwara ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Healthy Individuals ◽  
Low Frequencies ◽  
Healthy Donors ◽  
Before And After ◽  
Ifn Γ

Abstract Antigens implicated in the graft-versus-leukemia (GVL) effect in chronic myeloid leukemia (CML) include WT1, PR1, and BCR-ABL. To detect very low frequencies of these antigen-specific CD8+ T cells, we used quantitative polymerase chain reaction (qPCR) to measure interferon-γ (IFN-γ) mRNA production by peptide-pulsed CD8+ T cells from HLA-A*0201+ healthy volunteers and from patients with CML before and after allogeneic stem cell transplantation (SCT). Parallel assays using cytomegalovirus (CMV) pp65 tetramers demonstrated the IFN-γ copy number to be linearly related to the frequency of tetramer-binding T cells, sensitive to frequencies of 1 responding CD8+ T cell/100 000 CD8+ T cells. Responses to WT1 and PR1 but not BCR-ABL were detected in 10 of 18 healthy donors. Responses to WT1, PR1, or BCR-ABL were observed in 9 of 14 patients with CML before SCT and 5 of 6 after SCT, often to multiple epitopes. Responses were higher in patients with CML compared with healthy donors and highest after SCT. These antigen-specific CD8+ T cells comprised central memory (CD45RO+CD27+CD57–) and effector memory (CD45RO–CD27–CD57+) T cells. In conclusion, leukemia-reactive CD8+ T cells derive from memory T cells and occur at low frequencies in healthy individuals and at higher frequencies in patients with CML. The increased response in patients after SCT suggests a quantitative explanation for the greater effect of allogeneic SCT.

Lenalidomide as Salvage Therapy after Allogeneic Stem′Cell Transplantation in Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3704-3704
Author(s):  
Friederike Lehmann ◽  
Jean El-Cheikh ◽  
Tatjana Zabelina ◽  
Francis Ayuk ◽  
Christine Wolschke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Dose Reduction ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Optimal Dose ◽  
Hematological Toxicity ◽  
Once Daily ◽  
Grade 3

Abstract Lenalidomide is an immunmodulatory drug, orally administered once daily, which is effective in relapsed multiple myeloma (MM). Here, we evaluated the efficacy and toxicity of lenalidomide in 24 MM patients with relapsed disease after allogeneic stem cell transplantation (allo-SCT). Median age was 59 (range, 37–70) years. The series included 8 females and 16 males. Prior to allo-SCT, all patients were heavily pretreated with a median of 6 chemotherapy cycles including autologous and allo-SCT in all patients. Also, prior to lenalidomide, salvage treatment included donor lymphocyte infusions (DLI) in 18 pts,, thalidomide in 11 pts and bortezomib in 13 pts. Lenalidomide was given at 15mg (n=4) or 25 mg (n=20) orally once daily on day 1–21 every 28 days and in 20 patients in combination with dexamethason.. No prophylactic anticoagulation was used. The median number of completed cycles was 5 (range 2–17). Myelotoxicity according NCI criteria was the primarily and major encountered side effect (leukopenia: 4% grade 4, 21% grade 3, 17% grade 2, thrombopenia: 17% grade 3, 29% grade 2) and led to dose reduction in 54% of the patients. Infectious complications were observed in 50%. Non-hematological toxicity consisted of cramps (n=9), fatique (n=5) and constipation (n=2). Thrombembolic complications (cerebral infarction) were observed in one patient, who received concomitant corticosteroid treatment for acute graft-vs.-host disease (GvHD), but neurological symptoms resolved completely. GvHD of the skin under lenalidomide treatment was seen in 3 patients (one grade 2, and 2 grade 1), with one case occurring shortly after an additional DLI.. Objective remission was achieved in 66% of the patients (CR: 8%, VGPR: 8%, PR: 50%) and stable disease (SD) in 13% of the patients, while in 21% progressive disease was noted. Prior treatment with thalidomide or with bortezomib did not influenced the rate of CR/PR. Surprisingly, patients with del 13q14 achieved a higher CR/PR rate than those without del 13q14 (p=0.02). The median time to progression was 9.7 months (95% CI: 7.5–11.9) and the median overall survival was 19.9 months (95% CI: 17.3–22.5). Lenalidomide is effective in relapsed patients with MM after allo-SCT. Major toxicity is myelotoxicity, which required dose reduction in the majority of patients. The optimal dose of lenalidomide after allo-SCT has to be investigated.

Significant Changes in Inducible Cytokine Synthesis by Activated Peripheral Blood Leukocytes of Multiple Myeloma Patients Receiving Standard Dose Autologous Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5096-5096
Author(s):  
Bang-Ning Lee ◽  
Nina Shah ◽  
Sergio Giralt ◽  
Hui Gao ◽  
Evan N Cohen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Standard Dose ◽  
Symptom Burden ◽  
High Dose ◽  
Cd34 Cells ◽  
Tnf Α

Abstract Abstract 5096 Multiple myeloma (MM) is an incurable cancer characterized by the clonal proliferation of plasma cells within the bone marrow. We previously reported a positive correlation between serum levels of inflammatory cytokines and the severity of the self-reported symptoms in MM patients undergoing high dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT). As cytokines produced by activated peripheral blood (PB) leukocytes are likely to increase the severity of self-reported symptoms, we determined the ability of PB CD4+ and CD8+ T-lymphocytes, and CD14+ monocytes to produce cytokines following activation through the T-cell receptor (TCR) with anti-CD3 antibodies and toll-like receptor-4 with lipopolysaccharide (LPS), respectively. We studied 24 patients (65 yrs ± 7 yrs) with Durie-Salmon stages II/III MM, 15 men and 9 women; 18 Caucasian, 2 Hispanic, and 3 African-American and 1 Asian. All patients were part of an ongoing clinical trial studying high versus standard dose of autologous stem cells (AutoSC) during HDC followed by auto-SCT. All patients received standard high dose melphalan (200 mg/m2 in 2 divided doses) as their myeloablative chemotherapy. Fourteen subjects received a standard dose (SD) of AutoSC (4–6×106 CD34+ cells/kg) and 10 patients received a high dose (HD) of AutoSC (10–15×106 CD34+ cells/kg). The ability of TCR-activated CD4+ and CD8+ T cells to synthesize cytokines (Th1: IL-2, TNF-α, and IFN-γ; Th2: IL-4, and IL-10) and LPS-activated monocytes to synthesize IL-1β, IL-6, IL-8, IL-12, MCP-1, and TNF-a was assessed prior to auto-SCT and thereafter at 2 weeks, 1, 2, 6 and 12 months by multi-color flow cytometry assays. Friedman test was used to determine the differences in the percentages of cytokine-producing cells by each cohort across time. Wilcoxon tests were used as follow-up tests to determine at which time the differences exist. Mann-Whitney test was used to determine if there were differences in the percentages of leukocytes producing cytokines in patients who received SD or the HD of AuSC. The SD AuSC cohort had significant changes in the mean ± SEM percentages of TCR-activated CD3+CD8+ T cells that produced IL-2 and of CD3+CD4+ T cells that produced IL-10 across time. The increase in percentage of IL-2-producing T cells was followed by a significant decline (when compared with baseline) at 1-month post auto-SCT (14.5% ± 3.7% vs. 4.5% ± 1.3%; P = 0.019). This decline was sustained throughout the 12-month post auto-SCT and was attributable to CD3+CD8+ T cells (8.6% ± 2.3% vs 1.6% ± 0.4%; P = 0.013). Moreover, the SD cohort had an increase in the percentage of TCR-activated CD3+CD4+ T cells that synthesized IL-10 at 2 weeks post auto-SCT. Finally, the SD cohort also had a significant increase in the percentage of LPS-activated CD14+ monocytes that produced TNF-α at 3 months post auto-SCT when compared with LPS-activated CD14+ monocytes at baseline (0.6% ± 0.4% vs. 1.6% ± 0.4%; P = 0.006), and this increase was sustained over the remainder of 12-month period. These dynamic changes in cytokine production were not seen in the HD AuSC group. Moreover, there were no significant differences in the percentages of activated leukocytes synthesizing cytokines at any time point between the SD and HD AuSC groups. These preliminary results suggest that activated leukocytes from MM patients who received the SD of AuSC had a dysregulated cytokine profile while that of patients who received HD of AuSC did not. These significant changes may be associated with more variations in symptom burden of the SD cohort. Further analyses to correlate these findings with symptom burden are warranted to support this hypothesis. Disclosures: No relevant conflicts of interest to declare.

Recovery of KIR Expression After Allogeneic Stem Cell Transplantation in Multiple Myeloma Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4555-4555
Author(s):  
Thomas Stuebig ◽  
Michael Lioznov ◽  
Ulrike Fritsche-Friedland ◽  
Haefaa Alchalby ◽  
Christine Wolschke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Time Points ◽  
Kir Receptors

Abstract Abstract 4555 Introduction: Activating and inhibitory killer immunoglobulin like receptors (KIR) are predominantly expressed on natural killer (NK) cells. KIR mismatch allogeneic stem cell transplantation (alloSCT) has been reported to provide beneficial effects for Multiple Myeloma (MM). However, their recovery in MM patients remains poorly understood. We, therefore, analysed KIR recovery in 90 MM patients after alloSCT. Methods: KIR expression (CD158a/h, CD158b/b2, CD158e1/e2) on NK cells and T cell subsets was measured by flow cytometry at different time points after alloSCT. Results: During the first 90 days after alloSCT NK cells represent the largest lymphocyte subset. Activating receptors like NKp30 and NKp44 showed a fluctuating expression while members of the KIR family were expressed at a constant rate (20% of NK cells). There was no significant difference in the early post transplantation period (day 0–90) compared to later time points (day 360). In contrast, T cells showed increased KIR expression during the first 30 days after alloSCT, which was highly significant for CD158e (p=0,0001). After 30 days the expression declined to baseline. Furthermore, T cell activation marker HLA-DR reached its highest expression between days 60 and 90 when KIR receptors were expressed at their lowest level (27% vs. 8%, p < 0,0001). Conclusions: We conclude that KIR receptors were differentially expressed on NK and T cells. Because KIR receptors are constantly expressed by NK cells and NK cells are the most frequent lymphocyte populations early after alloSCT, NK cells may be useful for KIR mismatch cellular therapy. Disclosures: No relevant conflicts of interest to declare.

Influence Of Steroid Exposure On CMV Specific T Cells Following Allogeneic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5488-5488
Author(s):  
Cornelia S. Link ◽  
Elke Rücker-Braun ◽  
Sebastian Tuve ◽  
Sarah Matko ◽  
Marc Schmitz ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
High Dose ◽  
Virus Load ◽  
Cmv Disease ◽  
Cmv Reactivation

Abstract Introduction CMV-infection is a serious complication in patients after allogeneic stem cell transplantation (SCT) where immunosuppressive therapy and impaired T cell reconstitution result in a high risk for viral infections. Monitoring of CMV-virus load by PCR and preemptive therapy are important tools to prevent CMV disease. However, CMV specific cytotoxic T cells (CMV-CTLs) are needed to successfully control CMV-infections. CMV-specific multimers composed of the patients HLA Class I molecule bound to CMV pp65 epitopes give the possibility to monitor CMV-CTLs. Here, we present the case of CMV-reactivation following SCT for AML. Methods The percentage of CMV-specific CD8+ T cells was determined by flow cytometry and mapped to clinical and laboratory parameters of the patient. CD8+ T cells were detected using CD8-fluorescein isothiocyanate (FITC, Beckman Coulter) antibody and CD3 as a T-cell marker was labeled with CD3-allophycocyanin (APC, MACS Miltenyi Biotec) antibody. CMV-specific CD8+ T cells were detected using the CMV major histocompatibility complex (MHC) with Strep-Tactinphycoerythrin (PE) conjugate (Streptamers, IBA GmbH). Case A 60 years old male patient was diagnosed with acute myeloid leukemia (AML) with 95% myeloid blasts in the bone marrow and extramedullary AML manifestations at the time of diagnosis. Following induction therapy the patient was transplanted from a matched unrelated donor. The stem cell recipient as well as his donor had been tested sero-positive for CMV prior to SCT. Within the first month following transplantation, the patient developed an effective CMV specific immunity as seen by high levels of CMV-specific T cells (Figure 1). About three months following transplantation the patient was diagnosed with intestinal GVHD requiring high-dose glucocorticoid treatment. Following steroid exposure, levels of CMV-CTLs dropped and shortly thereafter rising CMV-copy numbers were observed which was accompanied by clinical signs of CMV enteritis. With the administration of antiviral treatment the CMV specific virus load decreased. However, levels of CMV-CTLs remained low, presumably as a result of ongoing steroid exposure. Discussion High levels of CMV-CTLs appeared to control CMV, as seen by a non-detectable virus load in standard PCR testing. The close correlation between the drop in CMV-CTL count and CMV activation highlights the potential of this method to monitor and understand immune responses to CMV following SCT. Of note, early presence of high frequencies of CMV-CTLs did not guarantee CMV-control under steroid exposure as seen in our case. Previous reports have suggested that high dose glucocorticoids may impact CMV-CTLs survival. This is supported by our case, where we see a rapid drop in CMV-CTLs following glucocorticoid exposure. However, the exact molecular mechanisms and more importantly, the predictive value of this finding remain elusive. Furthermore, these data suggest, that patients with ongoing high steroid exposure may not benefit from a transfer of CMV-specific T-cells to control CMV disease. Conclusion Further investigations to clarify the potential of CMV-CTL measurements and to understand the effect of steroid exposure at the functional level are warranted. Studies to correlate CMV-CTL counts with the level of immunosuppression and their influence on controlling CMV-disease will follow. In future, this tool could provide a chance to select patients at high risk of CMV reactivation who could profit from an individualized monitoring and early treatment. Disclosures: No relevant conflicts of interest to declare.

Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3690-3697 ◽  
Author(s):  
Evren Özdemir ◽  
Lisa S. St. John ◽  
Geraldine Gillespie ◽  
Sarah Rowland-Jones ◽  
Richard E. Champlin ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Immune Reconstitution ◽  
Cell Responses ◽  
Tetramer Staining ◽  
Cmv Reactivation ◽  
Cmv Antigenemia

Cytomegalovirus (CMV) infection causes significant morbidity and mortality in the setting of immunodeficiency, including the immune reconstitution phase following allogeneic stem cell transplantation (SCT). We assessed CMV-specific CD4+ and CD8+T-cell responses in 87 HLA-A*0201–positive (A2+) and/or B*0702-positive (B7+) allogeneic stem cell transplant recipients using HLA-peptide tetramer staining and cytokine flow cytometry (CFC) to examine the association of CMV-specific immune reconstitution and CMV antigenemia following SCT. Strong CMV-specific T-cell responses recovered in most subjects (77 of 87, 88%) after SCT. Frequencies of CMV-specific CD8+ T cells were significantly higher in those subjects who experienced early antigenemia relative to those who did not (2.2% vs 0.33%, P = .0002), as were frequencies of CMV-specific CD4+ T cells (1.71% vs 0.75%,P = .002). Frequencies of CMV-specific CD8+ T cells were also higher in subjects experiencing late antigenemia (2.4% vs 0.57%). When we combined tetramer staining and an assessment of cytokine production in a single assay, we found that individuals who experienced CMV antigenemia had lower tumor necrosis factor-α (TNF-α)–producing fractions of tetramer-staining CMV-specific CD8+ T cells than subjects who did not (25% vs 65%,P = .015). Furthermore, individuals at high risk for CMV reactivation, including patients with acute graft-versus-host disease and those receiving steroids, had low fractions of cytokine-producing CMV-specific CD8+ T cells (25% and 27%, respectively). These data suggest that the inability to control CMV reactivation following allogeneic SCT is due to the impaired function of antigen-specific CD8+ T cells rather than an inability to recover sufficient numbers of CMV-specific T cells.

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