An Accelerated CD8+, but Not CD4+, T-Cell Reconstitution Associates with a More Favorable Outcome Following HLA-Haploidentical HSCT: Results from a Retrospective Study of the Cell Therapy and Immunobiology Working Party of the EBMT

Abstract Introduction and Aim: HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is increasingly offered to patients with high-risk acute myeloid (AML) or lymphoid leukemia (ALL). Unfortunately, graft manipulation employed to overcome the HLA barrier significantly delays immune reconstitution, posing the patients at risk of infections. Accordingly, non-relapse mortality after haplo-HSCT clearly extends beyond day 100 post-transplant. Over the years, different approaches have been investigated to speed-up immune reconstitution. In the absence of validated immune biomarkers, it is however difficult to evaluate the clinical impact of accelerated immune reconstitution. The aim of this EBMT retrospective study is to explore immune-cell counts early after haplo-HSCT as predictive of its overall outcome. Methods and Patients: Among AML and ALL patients in the EBMT database who underwent haplo-HSCT in the period 2001-2012, criteria for study entry were survival beyond day 100 and availability of differential immune-cell counts (CD3+, CD4+, CD8+ T cells, CD19+ B cells, CD16+/CD56+ NK cells) within this period. Accordingly, statistical analysis was landmarked at day 100. Of 259 patients meeting these criteria (age 2-70, median 33), 67 (26%) were children. The underlying disease was AML in 162 cases (63%), while ALL in the remaining (including 5 cases of bi-phenotypic leukemia). Fifty-two percent of patients were transplanted in CR1. The stem-cell source was G-CSF mobilized peripheral blood in all but one patient (>99%) and 171 received TBI (66%). The graft was manipulated in 199 patients (78%), including CD34-selection (50%), ex vivo T-cell depletion (15%) or both (13%). Female-to-male transplants were 68 (26%), while 204 (79%) recipients were CMV seropositive. Sustained hematopoietic engraftment was reached in 246 patients (95%) Results: The estimated overall survival at 2yrs was43%. The estimated cumulative incidence of death due to relapse was 33%, while that of death due to other causes was 35% (51% of those were infections) The occurrence of grade III-IV GVHD and of chronic GVHD was 9% and 18% (7% extensive), respectively. As expected, overall survival was better in children (62% vs 36%, P=0.002 by Log-rank), who clearly had a lower incidence of death due to causes other than relapse compared with adults (10% vs 37%, P=0.0001). Negative prognostic factors for overall survival were any disease state other than CR1 at time of transplantation (P=0.002) and CMV seropositivity (P=0.009). Type of leukemia, TBI or graft manipulation had no effect on the outcome. By day 100 post-transplant, patients reached the following median immune-cell counts: 100 CD3+ T cells (range 0-2576), 30 CD4+ T cells (0-1714), 48 CD8+ T cells (0-1880), 276 CD16+/CD56+ NK cells (18-3581), 21 CD19+ B cells (0-790). Importantly, CD3+ counts above the first quartile (1Q) of the entire data set (29 cells per microL) were significantly associated with a better overall survival (P=0.0005 by Log rank) and a lower incidence of death due to causes other than relapse (P=0.002 by Gray test). The same held true for CD8+ counts (1Q: 15 cells per microL; P=0.003 on overall survival; P=0.0004 on death due to other causes). CD4+ counts also showed similar correlations, but at higher values (above the median). None of the other immune-cell counts analyzed correlated with clinical outcome. Strikingly, when challenged in multivariate analysis taking into account age category, CMV seropositivity, graft manipulation and CR1 status at transplant, CD3+ and CD8+ counts above the 1Q adjusted to fit optimal cut-off points were still significantly associated with a better overall survival (P=0.006 and P=0.015, respectively), but only CD8+ values associated with a lesser risk of death due to causes other than relapse (P=0.026). Conversely, similarly adjusted median CD4+ counts failed to show any association. Conclusions: Contrary to what is generally accepted, these results indicate that an accelerated CD8+, but not CD4+, T cell reconstitution associates with a more favorable clinical outcome after haplo-HSCT, likely due to its protective role against opportunistic viral infections. Moreover, they suggest that yet to be validated CD8+ cut-off points, rather than the commonly used arbitrary value of 200 CD4+ T cells per microL, should be considered as surrogate biomarkers in clinical trials. Disclosures Bonini: MolMed S.p.A: Consultancy.

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Kinetics of immune cell reconstitution predict survival in allogeneic bone marrow and G-CSF–mobilized stem cell transplantation

Blood Advances ◽

10.1182/bloodadvances.2018029892 ◽

2019 ◽

Vol 3 (15) ◽

pp. 2250-2263 ◽

Cited By ~ 10

Author(s):

Edmund K. Waller ◽

Brent R. Logan ◽

Mingwei Fei ◽

Stephanie J. Lee ◽

Dennis Confer ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Immune Reconstitution ◽

Acute Gvhd ◽

Immune Cell ◽

Blood Samples ◽

T Cell Reconstitution

Abstract The clinical utility of monitoring immune reconstitution after allotransplant was evaluated using data from Blood and Marrow Transplant Clinical Trials Network BMT CTN 0201 (NCT00075816), a multicenter randomized study of unrelated donor bone marrow (BM) vs granulocyte colony-stimulating factor (G-CSF)–mobilized blood stem cell (G-PB) grafts. Among 410 patients with posttransplant flow cytometry measurements of immune cell subsets, recipients of G-PB grafts had faster T-cell reconstitution than BM recipients, including more naive CD4+ T cells and T-cell receptor excision circle–positive CD4+ and CD8+ T cells at 3 months, consistent with better thymic function. Faster reconstitution of CD4+ T cells and naive CD4+ T cells at 1 month and CD8+ T cells at 3 months predicted more chronic graft-versus-host disease (GVHD) but better survival in G-PB recipients, but consistent associations of T-cell amounts with GVHD or survival were not seen in BM recipients. In contrast, a higher number of classical dendritic cells (cDCs) in blood samples at 3 months predicted better survival in BM recipients. Functional T-cell immunity measured in vitro by cytokine secretion in response to stimulation with cytomegalovirus peptides was similar when comparing blood samples from BM and G-PB recipients, but the degree to which acute GVHD suppressed immune reconstitution varied according to graft source. BM, but not G-PB, recipients with a history of grades 2-4 acute GVHD had lower numbers of B cells, plasmacytoid dendritic cells, and cDCs at 3 months. Thus, early measurements of T-cell reconstitution are predictive cellular biomarkers for long-term survival and response to GVHD therapy in G-PB recipients, whereas more robust DC reconstitution predicted better survival in BM recipients.

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OS1.6 Peripheral blood immune profiles at first recurrence of IDH wild type glioblastoma after standard chemoradiotherapy predict overall survival: secondary analyses of the phase II DIRECTOR trial

Neuro-Oncology ◽

10.1093/neuonc/noz126.019 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii6-iii7

Author(s):

H Wirsching ◽

E Terksikh ◽

S Manuela ◽

K Carsten ◽

R Patrick ◽

...

Keyword(s):

Overall Survival ◽

T Cells ◽

Prognostic Factors ◽

T Cell ◽

Peripheral Blood ◽

Immune Cell ◽

Cd4 T Cell ◽

Cox Models ◽

First Recurrence ◽

Cell Fractions

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) wildtype glioblastoma is associated with distinctive peripheral blood immune cell profiles that evolve under first line chemoirradiation with temozolomide. Whether peripheral blood immune cell profiles at recurrence are associated with survival of IDH wildtype glioblastoma has not been studied in detail. PATIENTS AND METHODS Peripheral blood mononuclear cells (PBMC) of 21 healthy donors and of 52 clinically well-annotated patients with IDH wildtype glioblastoma were analyzed by 11-color flow cytometry at 1st recurrence after standard chemoirradiation with temozolomide and at 2nd recurrence after dose-intensified temozolomide re-challenge. Patients were treated within the randomized phase II trial DIRECTOR, which explored the efficacy of dose-intensified temozolomide at first recurrence of glioblastoma. Patients were classified based on unsupervised analyses of PBMC profiles at 1stand 2ndrecurrence. Associations with survival were explored in multivariate Cox models controlling for established prognostic and predictive factors. RESULTS At 1strecurrence, two patient clusters were identified which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. The composition of CD4+, CD8+ or regulatory T-cell fractions was similar in both clusters. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by established prognostic factors, including age, O6-methylguanine-DNA-methyl-transferase (MGMT) gene promoter methylation, tumor volume, Karfnosky performance score or steroid use. Progression-free survival was similar (CD4high vsCD4low 2.1 vs 2.4 months, p=0.19), whereas post-recurrence overall survival was longer among the CD4highcluster (12.7 vs 8.7 months, p= 0.004). At 2nd recurrence, monocyte fractions increased, whereas memory CD4+ T-cell fractions decreased. Unsupervised segregation of patients by CD4+ subpopulations yielded two clusters characterized by the abundance of memory T-cell fractions and higher memory CD4+ fractions were associated with longer overall survival at 2nd recurrence (p=0.004). The reported prognostic associations were retained in multivariate Cox models controlling for established prognostic factors. CONCLUSION We conclude that temozolomide-associated memory CD4+ T-cell depletion may have deteriorating effects on the survival of glioblastoma patients.

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Post-Transplant Cyclophosphamide Ameliorates Lethal Thymic GVHD By Restoring Regulatory and Effector T Cell Homeostasis in Recipients with Prior PD-1 Blockade Therapy

Blood ◽

10.1182/blood-2018-99-111142 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 479-479

Author(s):

Shuntaro Ikegawa ◽

Yusuke Meguri ◽

Takumi Kondo ◽

Hiroyuki Sugiura ◽

Yasuhisa Sando ◽

...

Keyword(s):

Overall Survival ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Immune Reconstitution ◽

T Cell Subsets ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Donor T Cells ◽

The Impact

Abstract Allogeneic HSCT has a curative potential for patients with hematological malignancies. However, graft-versus-host disease (GVHD) remains to be a significant cause of morbidity and mortality after HSCT. Regulatory T cells (Tregs) are critical mediator for immune tolerance after HSCT and we recently reported that PD-1 plays an essential role for Treg survival (Asano et al, Blood 2017). Clinical studies suggested that PD-1 blockade prior to HSCT could be a risk of increasing severe GVHD. However, the mechanisms about GVHD induced by PD-1 blockade have largely unclear and there remains a paucity of data on appropriate GVHD prophylaxis for patients who undergo HSCT after PD-1 blockade. To address these issues, we investigated the impact of PD-1 expression on donor T cells on immune reconstitution with murine BMT models. First, lethally irradiated B6D2F1 mice were transplanted with 10 million of C57BL/6-background PD-1+/+ or PD-1-/- spleen cells with 5 million of bone marrow cells from normal C57BL/6, and GVHD scores and overall survival was monitored. Recipients receiving PD-1-/- graft developed severe GVHD resulting in a significant shorter survival than recipients receiving PD-1-/- graft (P<0.0001). We analyzed lymphocytes in spleen and thymus on day3, 7, and 14. We found that CD8 T cells in PD-1-/- group showed markedly higher Ki67 expression and CFSE-dilution until day3. Interestingly, PD-1-/- Tregs increased aggressively at day3 but it could not maintain until day14, while PD-1-/- CD8 T cells and conventional CD4 T cells (CD4 Tcons) continued to increase until day+14, resulting in the significant higher CD8/Treg ratio in PD-1-/- group (P<0.05, vs PD-1+/+ group). PD-1-/- Tregs showed significantly higher expression of Annexin V on day+7 and thymus CD4- and CD8- double-positive (DP) cells were in the extremely low levels in PD-1-/- group on day+14 (P<0.05, vs PD-1+/+ group). Thymic analysis showed that donor PD-1-/- graft-derived CD8 T cells infiltrated thymus in PD-1-/- group, suggesting reconstruction of thymic function was critically disturbed by severe GVHD. These data suggest that loss of PD-1 signaling resulted in unbalanced reconstitution of donor-derived T cell subsets as a consequence of continuous CTL expansion and increased Treg apoptosis. Next, to evaluate the impact of post-transplant cyclophosphamide (PTCy) on the abnormal reconstitution after PD-1 blockade, we administered 50mg/kg of Cy or control vehicle on day3. PTCy efficiently ameliorated GVHD in PD-1-/- group and extended overall survival by safely regulating the proliferation and apoptosis of T cell subsets. Of note, after PTCy, Tregs regained the ability of continuous proliferation in the first 2 weeks, resulting in well-balanced reconstitution of donor-derived T cell subsets. Thymic DP cells on day 14 was markedly increased in PD-1-/- group with PTCy intervention as compared to without PTCy, suggesting PTCy could rescue thymus from PD-1 blockade-related severe GVHD. Finally, to evaluate GVL activity, we performed BMT with co-infusion of P815L tumor cells on day0 and we confirmed that PTCy treatment for PD-1-/- recipients reduced the severity of GVHD with maintaining sufficient GVL effect. In summary, our data suggested three insights about the impact of PD-1 signaling on immune reconstitution. First, PD-1 inhibition influenced graft-derived T cells very differently within T cell subsets. PD-1-/- Tregs increased transiently but it was counterbalanced by accelerated apoptosis, while PD-1-/- CD4+Tcons and CD8 T cells continued the drastic expansion. Second, we found that PD-1-/- donor T cells developed severe GVHD in thymus. Few reports have concentrated on the impact of donor graft PD-1 expression to thymus after BMT and acute GVHD in thymus could lead late central immune disturbance. Third, PTCy successfully ameliorated GVHD induced by PD-1-/- donor T cells preserving GVL effect. Cell proliferation study implied that PD-1-/- graft-derived CD8 T cells might be more susceptible for PTCy because of the high-rate proliferation. In conclusion, PD-1-/- graft cause lethal thymic GVHD and PTCy successfully ameliorated it. The influence of PD-1 inhibition was different within T cell subtypes. PTCy might be appropriate GVHD prophylaxis strategy for patients who had prior usage of PD-1 blockade. Disclosures No relevant conflicts of interest to declare.

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Rapid Helper T-Cell Recovery at 3 Months Correlates to Successful Transplant Outcomes after Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v106.11.5201.5201 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5201-5201

Author(s):

Joon Ho Moon ◽

Jin Ho Baek ◽

Dong Hwan Kim ◽

Sang Kyun Sohn ◽

Jong Gwang Kim ◽

...

Keyword(s):

Overall Survival ◽

T Cells ◽

T Cell ◽

Immune Reconstitution ◽

Opportunistic Infections ◽

Helper T Cells ◽

Cell Recovery ◽

Helper T Cell ◽

Post Transplant ◽

Cell Counts

Abstract Background: The current study attempted to evaluate the role of a simple quantitative measurement of peripheral lymphocyte subsets, especially CD4+ helper T-cell recovery, in predicting transplant outcomes, including overall survival (OS), non-relapse mortality (NRM), and opportunistic infections, after allogeneic stem cell transplantation (SCT). Methods: A total of 69 patients receiving an allogeneic SCT were included. The disease entities were as follows: AML 42, ALL 5, CML 15, NHL 5, and high-risk MDS 2. The peripheral lymphocyte subset counts, such as CD3+ T-cells, CD3+4+ helper T-cells, CD3+8+ cytotoxic T-cells, CD19+ B-cells, and CD56+ natural killer (NK) cells, were measured 3, 6, and 12 months post-transplant. Results: The CD19+ B-cell reconstitution was slow, while a rapid CD56+ NK cell recovery was noted. The CD4+ helper T-cell reconstitution at 3 months was strongly correlated with OS (p<0.0001), NRM (p=0.0007), and opportunistic infections (p=0.0108) when stratifying patients with cut-off value of 200×106/L CD4+ helper T-cells. A rapid CD4+ helper T-cell recovery was also independently associated with a higher CD4+ helper T-cell transplant dose (p=0.006) and donor type (p<0.001) in a regression analysis. An early CD4+ helper T-cell recovery at 3 months was associated with a subsequent faster helper T-cell recovery until 12 months, yet not with B-cell recovery. In a multivariate survival analysis, a combination of a higher CD34+ cell dose and rapid recovery of CD4+ helper T-cells at 3 months was found to a have favorable prognosis in terms of OS (p=0.001, hazard ratio [HR] 3.653) and NRM (p=0.005, HR 4.836), yet not relapse. Conclusion: A rapid recovery of the CD4+ helper T-cell count above 200×106/L at 3 months seemed to correlate with a faster immune reconstitution and predict a successful transplant outcome. Figure. The overall survival according to the helper T-cell counts at 3 months (A) and the difference of total T-(B) and helper T-cell (C) immune reconstitution within 1-year post-transplant according to helper T-cell counts at 3 months Figure. The overall survival according to the helper T-cell counts at 3 months (A) and the difference of total T-(B) and helper T-cell (C) immune reconstitution within 1-year post-transplant according to helper T-cell counts at 3 months

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Robust CD4+ T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin

Blood Advances ◽

10.1182/bloodadvances.2019000836 ◽

2020 ◽

Vol 4 (1) ◽

pp. 191-202 ◽

Cited By ~ 7

Author(s):

Ioannis Politikos ◽

Jessica A. Lavery ◽

Patrick Hilden ◽

Christina Cho ◽

Taylor Borrill ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cord Blood ◽

Cd8 T Cells ◽

Antithymocyte Globulin ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Cell Recovery ◽

Cell Counts

Abstract Quality of immune reconstitution after cord blood transplantation (CBT) without antithymocyte globulin (ATG) in adults is not established. We analyzed immune recovery in 106 engrafted adult CBT recipients (median age 50 years [range 22-70]) transplanted for hematologic malignancies with cyclosporine/mycophenolate mofetil immunoprophylaxis and no ATG. Patients were treated predominantly for acute leukemia (66%), and almost all (96%) underwent myeloablation. Recovery of CD4+ T cells was faster than CD8+ T cells with median CD4+ T-cell counts exceeding 200/mm3 at 4 months. Early post-CBT, effector memory (EM), and central memory cells were the most common CD4+ subsets, whereas effector and EM were the most common CD8+ T-cell subsets. Naive T-cell subsets increased gradually after 6 to 9 months post-CBT. A higher engrafting CB unit infused viable CD3+ cell dose was associated with improved CD4+ and CD4+CD45RA+ T-cell recovery. Cytomegalovirus reactivation by day 60 was associated with an expansion of total, EM, and effector CD8+ T cells, but lower CD4+ T-cell counts. Acute graft-versus-host disease (aGVHD) did not significantly compromise T-cell reconstitution. In serial landmark analyses, higher CD4+ T-cell counts and phytohemagglutinin responses were associated with reduced overall mortality. In contrast, CD8+ T-cell counts were not significant. Recovery of natural killer and B cells was prompt, reaching medians of 252/mm3 and 150/mm3 by 4 months, respectively, although B-cell recovery was delayed by aGVHD. Neither subset was significantly associated with mortality. ATG-free adult CBT is associated with robust thymus-independent CD4+ T-cell recovery, and CD4+ recovery reduced mortality risk.

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Reconstitution of Peripheral T Cells by Tissue-Derived CCR4+ Central Memory Cells Following HIV-1 Antiretroviral Therapy

Pathogens and Immunity ◽

10.20411/pai.v1i2.129 ◽

2016 ◽

Vol 1 (2) ◽

pp. 260 ◽

Cited By ~ 8

Author(s):

Yolanda D. Mahnke ◽

Kipper Fletez-Brant ◽

Irini Sereti ◽

Mario Roederer

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Antiretroviral Therapy ◽

Cd8 T Cells ◽

Plasma Viral Load ◽

Cd4 T Cell ◽

Cell Numbers ◽

Cell Counts ◽

Hiv 1

Background. Highly active antiretroviral therapy induces clinical benefits to HIV-1 infected individuals, which can be striking in those with progressive disease. Improved survival and decreased incidence of opportunistic infections go hand in hand with a suppression of the plasma viral load, an increase in peripheral CD4+ T-cell counts, as well as a reduction in the activation status of both CD4+ and CD8+ T cells.Methods. We investigated T-cell dynamics during ART by polychromatic flow cytometry in total as well as in HIV-1-specific CD4+ and CD8+ T cells. We also measured gene expression by single cell transcriptomics to assess functional state.Results. The cytokine pattern of HIV-specific CD8+ T cells was not altered after ART, though their magnitude decreased significantly as the plasma viral load was suppressed to undetectable levels. Importantly, while CD4+ T cell numbers increased substantially during the first year, the population did not normalize: the increases were largely due to expansion of mucosal-derived CCR4+ CD4+ TCM; transcriptomic analysis revealed that these are not classical Th2-type cells.Conclusion. The apparent long-term normalization of CD4+ T-cell numbers following ART does not comprise a normal balance of functionally distinct cells, but results in a dramatic Th2 shift of the reconstituting immune system.

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The effect of tuberculosis on immune reconstitution among HIV patients on highly active antiretroviral therapy in Adigrat general hospital, eastern Tigrai, Ethiopia; 2019: a retrospective follow up study

BMC Immunology ◽

10.1186/s12865-019-0327-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 2

Author(s):

Hadush Negash ◽

Haftom Legese ◽

Mebrahtu Tefera ◽

Fitsum Mardu ◽

Kebede Tesfay ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Highly Active Antiretroviral Therapy ◽

Cd4 T Cells ◽

Immune Reconstitution ◽

Cd4 T Cell ◽

Highly Active ◽

Cell Counts

Abstract Background Ethiopia initiated antiretroviral therapy early in 2005. Managing and detecting antiretroviral treatment response is important to monitor the effectiveness of medication and possible drug switching for low immune reconstitution. There is less recovery of CD4+ T cells among human immunodeficiency virus patients infected with tuberculosis. Hence, we aimed to assess the effect of tuberculosis and other determinant factors of immunological response among human immunodeficiency virus patients on highly active antiretroviral therapy. A retrospective follow up study was conducted from October to July 2019. A total of 393 participants were enrolled. An interviewer based questionnaire was used for data collection. Patient charts were used to extract clinical data and follow up results of the CD4+ T cell. Current CD4+ T cell counts of patients were performed. STATA 13 software was used to analyze the data. A p-value ≤0.05 was considered a statistically significant association. Results The mean age of study participants was 39.2 years (SD: + 12.2 years) with 8.32 mean years of follow up. The overall prevalence of immune reconstitution failure was 24.7% (97/393). Highest failure rate occurred within the first year of follow up time, 15.7 per 100 Person-year. Failure of CD4+ T cells reconstitution was higher among tuberculosis coinfected patients (48.8%) than mono-infected patients (13.7%). Living in an urban residence, baseline CD4+ T cell count ≤250 cells/mm3, poor treatment adherence and tuberculosis infection were significantly associated with the immunological failure. Conclusions There was a high rate of CD4+ T cells reconstitution failure among our study participants. Tuberculosis infection increased the rate of failure. Factors like low CD4+ T cell baseline count, poor adherence and urban residence were associated with the immunological failure. There should be strict monitoring of CD4+ T cell counts among individuals with tuberculosis coinfection.

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Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

Journal of Virology ◽

10.1128/jvi.00789-15 ◽

2015 ◽

Vol 89 (15) ◽

pp. 7829-7840 ◽

Cited By ~ 24

Author(s):

Selena Vigano ◽

Jordi Negron ◽

Zhengyu Ouyang ◽

Eric S. Rosenberg ◽

Bruce D. Walker ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Stem Cell ◽

T Cell ◽

Antiretroviral Therapy ◽

Cd8 T Cells ◽

Cd4 T Cell ◽

Cell Counts ◽

Cellular Immune ◽

Hiv 1

ABSTRACTHIV-1-specific CD8 T cells can influence HIV-1 disease progression during untreated HIV-1 infection, but the functional and phenotypic properties of HIV-1-specific CD8 T cells in individuals treated with suppressive antiretroviral therapy remain less well understood. Here we show that a subgroup of HIV-1-specific CD8 T cells with stem cell-like properties, termed T memory stem cells (TSCMcells), is enriched in patients receiving suppressive antiretroviral therapy compared with their levels in untreated progressors or controllers. In addition, a prolonged duration of antiretroviral therapy was associated with a progressive increase in the relative proportions of these stem cell-like HIV-1-specific CD8 T cells. Interestingly, the proportions of HIV-1-specific CD8 TSCMcells and total HIV-1-specific CD8 TSCMcells were associated with the CD4 T cell counts during treatment with antiretroviral therapy but not with CD4 T cell counts, viral loads, or immune activation parameters in untreated patients, including controllers. HIV-1-specific CD8 TSCMcells had increased abilities to secrete interleukin-2 in response to viral antigen, while secretion of gamma interferon (IFN-γ) was more limited in comparison to alternative HIV-1-specific CD8 T cell subsets; however, only proportions of IFN-γ-secreting HIV-1-specific CD8 TSCMcells were associated with CD4 T cell counts during antiretroviral therapy. Together, these data suggest that HIV-1-specific CD8 TSCMcells represent a long-lasting component of the cellular immune response to HIV-1 that persists in an antigen-independent fashion during antiretroviral therapy but seems unable to survive and expand under conditions of ongoing viral replication during untreated infection.IMPORTANCEMemory CD8 T cells that imitate the functional properties of stem cells to maintain lifelong cellular immunity have been hypothesized for many years, but only recently have such cells, termed T memory stem cells (TSCMcells), been physically identified and isolated in humans, mice, and nonhuman primates. Here, we investigated whether cellular immune responses against HIV-1 include such T memory stem cells. Our data show that HIV-1-specific CD8 T memory stem cells are detectable during all stages of HIV-1 infection but occur most visibly at times of prolonged viral antigen suppression by antiretroviral combination therapy. These cells may therefore be particularly relevant for designing antiviral immune defense strategies against the residual reservoir of HIV-1-infected cells that persists despite treatment and leads to viral rebound upon treatment discontinuation.

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Comparable Immune Reconstitution Achieved Following Unmanipulated HLA-Mismatched/Haploidentical Transplantation and HLA-Identical Sibling Transplantation

Blood ◽

10.1182/blood.v116.21.2312.2312 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2312-2312

Author(s):

Ying-Jun Chang ◽

Xiao Jun Huang ◽

Xiang-Yu Zhao ◽

Ming-Rui Huo ◽

Lan-Ping Xu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Human Leukocyte ◽

Cd4 T Cell ◽

Transplant Recipients ◽

Leukocyte Antigen ◽

Haploidentical Transplantation ◽

Cell Counts ◽

Time Point

Abstract Abstract 2312 Unmanipulated human leukocyte antigen (HLA)-mismatched/haploidentical trasnplantation is an established treatment for patients without HLA-matched related or unrelated donors. In contrast to HLA-matched transplant, intensified immnological suppression, including antithymocyte globulin was used to overcome the HLA barrier. However, it is currently unclear how this radically different transplantation strategy affect immunological recovery. To investigate the immune reconstituion following unmanipulated human leukocyte antigen (HLA)-mismatched/haploidentical trasnplantation and HLA-matched transplantation. Seventy-five patients underwent transplantation from either HLA-identical siblings (25 cases) or haploidentical donors (50 cases) were enrolled in this prospective study. Recovery of T-, B-, monocytes, and dendritic cell subsets, proliferative of T lymphocytes in vitro response to mitogens, were investigated. Our results showed that in the first 90 days after grafting, counts of the following T cell subsets were signifcantly lower in haploidentical transplant recipients than those of HLA-matched transplant recipients: total CD4+ T cells, and their CD45RA positive (naïve), CD45RO (memory) subpopulation. After this interval, increases in CD4+, CD4+ naïve, and CD4+ memory T cell counts were observed in surviving subjects, by 1 year after transplantation, there were no differences in the numbers of recovered CD4+, CD4+ naïve, and CD4+ memory T cells between patients receiving haploidentical transplant and those receiving HLA-identical transplantation. In contrast, total counts of CD8+ T cells declined after conditioning and were significantly reduced by day 30 post-haploidentical transplantation. Thereafter, absolute of CD8+ T cell numbers expanded dramatically, and were signifciantly higher than that of HLA-identical recipients since day 90 post transplantation time point (Figure). CD3+ cells, CD8+ naïve, and CD8+ memory T cells were comparable by 90 days after transplantation, although lower numbers of these cells were found in haploidentical group prior day 90 after grafting. Furthermore, the ratio of CD4/CD8 T cells was significantly inverted in both groups untill 1 year after transplantation. While monocytes recovered promptly and reached normal levels by day 15 after haploidentical transplantation, though they also declined slightly by the 1 year time point, at which CD4+ T cell counts rebounded. These results indciate that quantitative CD4+ T-cell recovery is delayed after haploidentical transplantation, they also suggest that compensatory expansion of cytotoxic T lymphocytes and monocytes may accompany CD4+ T lymphopenia. Subsets of DC, including myeloid DC 1 (MDC1), MDC2 and plasmacytoid DC (pDC), in haploidentical recipients on day 15, and day 30 post allografting were significantly lower than those in HLA-matched recipients. No sigificant difference in the counts of B cells at any time point after transplantation in haploidentical recipients and HLA-matched recipients were found. On day 15 after transplantation, the expression of CD28 on CD8+ T cells was sigificantly lower in patients receiving haploidentical transplantation, then increased promptly and signifcantly higher than those receiving HLA-matched transplant on day 30, and 90, after this two time point the expression of CD28 were comparable between two groups. Moreover, the expression of CD28 on CD4+ T cells was also signifcantly higher than those receiving HLA-matched transplant on day 30, and 90. While only at days 30 post transplant, the expession of CD80 on pDC were signifcantly higher in patients receiving haploidentical transplant and than those receiving HLA-identical transplantation. The ability of the patient-derived T cells to produce IFN-Ã and IL-4 by day 30 after transplantation was similar in in patients without aGVHD between haploidentical transplant recipients and HLA-matched recipients. Our results suggest that comparable immune reconstitution could be achieved folloing hapolidentical transplantation and HLA-matched transplantation, this is related to the similar transplant outcomes. Fig The capability of T cells to produce IFN-Ã and IL-4 in patients without aGVHD between HLA-matched transplantation (the former box) and haploidentical transplantation (the latter box). Fig. The capability of T cells to produce IFN-Ã and IL-4 in patients without aGVHD between HLA-matched transplantation (the former box) and haploidentical transplantation (the latter box). Disclosures: No relevant conflicts of interest to declare.

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Rapid Increase of CD8+ T Cell Count in Peripheral Blood of Pediatric Patients After HLA-Identical Stem Cell Transplantation for African Sickle Cell Anemia

Blood ◽

10.1182/blood.v120.21.4769.4769 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4769-4769

Author(s):

Antonella Isgrò ◽

Marco Marziali ◽

Pietro Sodani ◽

Javid Gaziev ◽

Daniela Fraboni ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cd4 T Cell ◽

Myeloablative Conditioning ◽

Cell Counts

Abstract Abstract 4769 Background. Sickle Cell anemia (SCA) remain a disease with high risk of morbidity and early death, especially in African patients. Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCA. To analyze immunohematological reconstitution after transplant, we report our experience concerning 12 geno-identical HSCT for SCA-patients prepared with the same myeloablative conditioning regiment consisting of Busulfan and Cyclophosphamide. Patients and Methods. Twelve patients with a median age of 12 years (range, 2–16), affected by sickle cell anemia (SCA), received hematopoietic stem cell transplantations from HLA-identical, related donors following a myeloablative conditioning regimen. To analyze the mechanisms involved in immunological reconstitution post transplant, we analyzed T cell subsets by flow cytometry at + 60 post transplant. Results. All patients had sustained engraftment and remained free of any SCA-related events after transplantation. Sixty days after the transplant, the patients had significantly lower CD4+ T cells in comparison to the controls (15.6 ± 5.9 % vs. 47.5 ± 6% respectively), whereas CD8+ T cells were the first lymphocytes to repopulate the peripheral blood with up to 45% of these cells being CD8+ T cells (in mean 48.5 ± 14.3 % vs. 20 ± 7%). All patients displayed reduced numbers of B cells versus normal value, and 10/12 patients had only 0% to 1% of control levels of CD19+ cells. CD3-CD56+bright NK cells were 18.6 ± 12.2 %, whereas CD3-CD16+ (with cytotoxic functions) were 16.7 ± 11.8 %. Conclusion. Our primary finding include the following: 1) rapid increase of lymphocytes in peripheral blood after transplant; 2) rapid expansion of CD8+ T cell but not CD4 T cell counts. Probably reactivation of cytomegalovirus (CMV) infection, observed in 11/12 patients on the early stages of T-lymphocyte recovery after transplant, might induce a dramatic increase in CD8 but not in CD4 T-cell counts. Disclosures: No relevant conflicts of interest to declare.

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