Immune reconstitution following autologous transfers of CD3/CD28 stimulated CD4+ T cells to HIV-infected persons

2004 ◽  
Vol 111 (3) ◽  
pp. 262-274 ◽  
Author(s):  
Wendy B. Bernstein ◽  
Josephine H. Cox ◽  
Naomi E. Aronson ◽  
LaRee Tracy ◽  
Katia Schlienger ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Immune Reconstitution

Immunology

2017 ◽  
Author(s):  
Dennis J. Hartigan-O’Connor ◽  
Christian Brander
Keyword(s):  
T Cells ◽  
Chronic Inflammation ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Opportunistic Infections ◽  
Cd4 T Cell ◽  
Elite Controllers ◽  
Gastrointestinal Mucosa ◽  
Key Factor ◽  
Hiv Antiretroviral Therapy

The key factor in HIV pathogenesis is the decline in CD4+ T cells with resultant immunodeficiency and chronic inflammation. Depletion of CD4+ T cells from the gastrointestinal mucosa followed by microbial translocation and subsequent immune activation are components of disease progression in untreated patients. Symptomatic and occult opportunistic infections including cytomegalovirus contribute to chronic inflammation in persons infected with HIV. Antiretroviral therapy (ART) results in immune reconstitution, with increases in peripheral CD4+ T cell lymphocytes in most persons infected with HIV, although immune recovery is quite variable. A subset of patients with AIDS will develop immune reconstitution inflammatory syndromes after initiation of ART. Approximately 1% of persons with HIV are able to control infection without the need for ART (“elite” controllers). A variety of immune-based therapies, including hydroxyurea, growth hormone, and statins, are being studied in clinical trials and may ultimately play a role in treating persons with HIV infection.

scholarly journals Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3818-3827 ◽  
Author(s):  
Lis R. V. Antonelli ◽  
Yolanda Mahnke ◽  
Jessica N. Hodge ◽  
Brian O. Porter ◽  
Daniel L. Barber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Interferon Γ ◽  
Effector Memory ◽  
Hiv Patients ◽  
Inflammatory Syndrome

Abstract Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1+, HLA-DR+, and Ki67+ CD4+ T cells than patients without IRIS. Moreover, PD-1+ CD4+ T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-γ, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials.gov as NCT00557570 and NCT00286767.

The Elevated Ratio of Peripheral Blood CD27−CD4+ T Cells in Patients Received Allogeneic Stem Cell Transplantation Implies Altered T Cell Homeostasis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1413-1413
Author(s):  
Akiko Fukunaga ◽  
Takayuki Ishikawa ◽  
Takero Shindo ◽  
Sumiko Takao ◽  
Toshiyuki Hori ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Cd4 T Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Effector Cells

Abstract One of the major problems following allogeneic stem cell transplantation (allo-SCT) is the inability to reconstitute an adequate immune system for an extended period. T-cell reconstitution is also delayed for years, especially in CD4+ T cells. In addition to impaired thymic function, shortened Naive T cell survival due to altered T cell homeostasis is reported to be responsible for delayed immune reconstitution. To further investigate the mechanisms of delayed immune recovery after allo-SCT, we focused on the frequencies of effector CD4+ T cells, because according to the previous reports, progressive linear differentiation model of CD4+ T cell predicts the accumulation of terminally differentiated effector cells when transition from naïve to memory T cells and memory to effector cells are accelerated. By flowcytometric analyses we confirmed that CD27−CD4+ T cells from allo-SCT recipients uniformly express CD95, with negative expression of CCR7 and CD62L. They also produce g-interferon (IFNg) in response to the immobilized anti-CD3 and soluble anti-CD28 stimulation, which is consistent with previous reports insisting that CD27−CD4+ T cells are functionally differentiated effector T cells. Measuring the ratio of CD27−CD4+ T cells among CD4+ T cells revealed that, although healthy donors and patients received allo-SCT within a year had comparable CD27+CD4+T-cell rate (90% vs. 83%, P=0.4436), significantly decreased rate was observed in patients transplanted more than 1 year before (55% vs. 83%, P=0.0005). The ratio of CD27+CD4+ T cells kept low during the first 5 years after allo-SCT, and then it slowly begun to increase. In addition, in patients who received stem cell grafts more than 1 year before, the ratio of CD27+CD4+ T cells were significantly higher in patients transplanted from HLA-matched siblings than in those received unrelated grafts (69% vs. 42%, P=0.0002). Other factors, such as stem cell source (BM or PBSC), patient age, and the presence of chronic GVHD did not influence the ratio of CD27+CD4+ T cells. To further investigate the characteristics of CD27−CD4+ T cells in post-transplant periods, peripheral CD4+ T cells from patients who had received allo-SCT more than 1 year before as well as healthy volunteers were sorted into CD27− and CD27+ fractions, stained with CFSE, and stimulated with immobilized anti-CD3 and soluble anti-CD28 antibodies. CD27−CD4+ T cells proliferated more vigorously at 3 days after stimulation, though after another 2-day culture, there was no difference in cell divisions between both cell groups. In addition, CD27+ cells from transplanted patients lost their expression more frequently than those from volunteers, while none of the CD27− cells stored its expression. The fact of one-way transition from CD27+ to CD27− also supported that CD27−CD4+ T cells are terminally differentiated T cells. The finding that the frequencies of CD27−CD4+ T cells begin to elevate at 1 year after allo-SCT indicates that T cells infused with allograft do not easily lose the surface expression of CD27, while T cells derived from donor’s stem cells do. Considering the fact that ratio of CD27−CD4+ T cells is much higher in recipients of unrelated grafts, and it gradually begin to decrease at 5 years after allo-SCT, the increased ratio of CD27−CD4+ T cells may reflect altered T cell homeostasis. The serial monitoring of the ratio of CD27−CD4+ T cells after allo-SCT may be useful in evaluating immune reconstitution status.

scholarly journals HIV Populations Shift After Tuberculosis Associated Immune Reconstitution Inflammatory Syndrome: Implications For HIV Remission

2020 ◽  
Author(s):  
Camille Lange ◽  
Maura Manion ◽  
Natalie Lindo ◽  
Robert Gorelick ◽  
Ana Ortega-Villa ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Reconstitution Inflammatory Syndrome ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Long Term Effects ◽  
Genetic Characteristics ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Infected Cells ◽  
Inflammatory Syndrome

Abstract Tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) is a serious complication of starting combination antiretroviral therapy (cART). TB-IRIS emerges early after cART initiation and is characterized by rapid expansions of TB-specific CD4+ T cells and high levels of inflammatory mediators driven by CD4+ T cells. The effects of TB-IRIS on HIV populations are unknown, but could result in profound expansion and elimination of HIV infected cells via cellular activation and acute inflammation. We investigated immediate and long-term effects of TB-IRIS on HIV infected cells with and without TB-IRIS. We measured plasma HIV RNA, cell-associated HIV RNA and HIV DNA levels and compared genetic characteristics of HIV populations after prolonged cART. We found that TB-IRIS was associated with more diverse HIV DNA populations and HIV reservoirs after IRIS were distinct from pre-therapy populations, suggesting that TB-IRIS can shape the HIV reservoir with detrimental implications for HIV remission strategies.

scholarly journals Cofilin hyperactivation in HIV infection and targeting the cofilin pathway using an anti-α4β7 integrin antibody

2019 ◽  
Vol 5 (1) ◽  
pp. eaat7911 ◽  
Author(s):  
Sijia He ◽  
Yajing Fu ◽  
Jia Guo ◽  
Mark Spear ◽  
Jiuling Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Motility ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Actin Dynamics ◽  
Lymphoid Tissues ◽  
Cell Recovery

A functional HIV cure requires immune reconstitution for lasting viremia control. A major immune dysfunction persisting in HIV infection is the impairment of T helper cell migration and homing to lymphoid tissues such as GALTs (gut-associated lymphoid tissues). ART (antiretroviral therapy) does not fully restore T cell motility for tissue repopulation. The molecular mechanism dictating this persistent T cell dysfunction is not understood. Cofilin is an actin-depolymerizing factor that regulates actin dynamics for T cell migration. Here, we demonstrate that blood CD4 T cells from HIV-infected patients (n = 193), with or without ART, exhibit significantly lower levels of cofilin phosphorylation (hyperactivation) than those from healthy controls (n = 100; ratio, 1.1:2.3; P < 0.001); cofilin hyperactivation is also associated with poor CD4 T cell recovery following ART. These results suggest an HIV-mediated systemic dysregulation of T cell motility that cannot be repaired solely by ART. We further demonstrate that stimulating blood CD4 T cells with an anti–human α4β7 integrin antibody can trigger signal transduction and modulate the cofilin pathway, partially restoring T cell motility in vitro. However, we also observed that severe T cell motility defect caused by high degrees of cofilin hyperactivation was not repairable by the anti-integrin antibody, demonstrating a mechanistic hindrance to restore immune functions in vivo. Our study suggests that cofilin is a key molecule that may need to be therapeutically targeted early for T cell tissue repopulation, immune reconstitution, and immune control of viremia.

Flagellin, a TLR5 Agonist, Down-Regulate CD62L on Donor T Cells and Limit GvHD in Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3521-3521
Author(s):  
Mohammad Hossain ◽  
Andrew T Gewirtz ◽  
John D Roback ◽  
Edmund K. Waller
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Major Complication ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Donor T Cells

Abstract Bacground: Graft-vs-host disease (GvHD) is a major complication in allogeneic Hematopoietic Stem Cell Transplant (HSCT) recipients. Flagellin is a bacterial protein and a TLR5 agonist that showed diverse immunological responses in both human and animal including both activation of dendritic cells and immuno-suppression. We recently observed that prophylactic use of flagellin protected allogeneic HSCT recipient from GvHD without affecting host immune reconstitution. Acute GvHD has been reported to be mediated by allo-reactive CD62L+ T cells, and over 80% of murine naïve splenic CD4+ and CD8+ T cells express CD62L. In order to test the effect of flagellin on GvHD mediated by the CD62L+ CD4+ and CD62L+CD8+ donor T cells, we investigated clinical manifestation of GvHD as well as the in vivo expression of CD62L on donor T cells in flagellin treated versus control treated allogeneic HSCT recipients. Methods: We established a parent →F1 MHC major mismatched model (C57BL/6 → C57BL/6 × BALB/c) for allogeneic HSCT for which GvHD is the major complication. Recipient mice received 5 × 10^6 T cell depleted (TCD) bone marrow cells and 5×10^6 or 10×10^6 CFSE labeled donor splenocytes from naïve C57Bl/6 congenic donors. 50 μg flagellin per recipient was administered intraperitoneally 3 hours before irradiation and 24 hours after allogeneic HSCT (treated). CB6F1 recipients that received no flagellin (untreated) and recipients of syngeneic HSCT were used as control. Recipients were sacrificed on day 66+ transplant and the numbers of CD62L+ T cells and foxp3+CD4+CD25+ T cells were determined by FACS. Recipients of CFSE treated donor splenocytes were sacrificed on day 4 post HSCT, splenocytes were harvested and analyzed for CD62L expression on T cell subsets undergone in vivo cell division by Flow cytometry. 5 mice were used per group. Results: Flagellin treated recipients did not have GvHD and had no mortality. Untreated control recipients had 87% survival at 30 days post transplant and had signs of chronic GvHD. While total cell number and also donor spleen- and BM-derived CD4+ and CD8+ T cells per spleen in untreated recipients were significantly lower compared to flagellin treated recipients (p=0.0006) on day 66 post transplant, persistent of donor spleen-derived CD62L+CD4+ T cells and CD62L+CD8+ T cells per spleen were not significantly different (p=0.13 and p=0.07, respectively). Moreover, higher number of foxp3+CD25+CD4+ regulatory T cells were found in the spleen and thymus in treated recipients compared to untreated recipients. Within day 4 post transplant, the number of CD4+ T cells per spleen of treated and untreated recipients increased significantly compared to syngeneic recipients (p=0.001 and p=0.03, respectively). Although equivalent numbers of CD62L+CD4+ T cells were observed in both treated and untreated recipients (p=0.3), significantly increased numbers of CD62L+CD8+ T cells was found in treated recipients compare to untreated recipients (p=0.02). Moreover, significantly higher numbers of divided (far left CFSE staining population) CD62L+CD4+ and CD62L+CD8+ T cells were found in recipients of treated splenocytes within day 4 post transplant followed by down regulation of CD62L surface marker compared to untreated recipients (p=0.02 and p=0.01, respectively). Conclusion: Flagellin treated recipients had limited GvHD and had rapid increased divided CD4+CD62L+ T cells followed by CD62L-ve activated CD4+ T cells per spleen in treated recipients compared to untreated recipients may be one of the major affect mediated by flagellin. Flagellin-TLR5 receptor agonistic effect may reduce production of biological factor(s) essential to generate allo-reactive T cells or directly stimulate CD62L+CD4+ and CD62L+CD8+ T cells in different activation status other than allo-reactive T cells; maintain a balanced immune reconstitution in lymphoid organs by producing regulatory T cells through their thymus. Therefore, use of flagellin may be a novel therapeutic approach to treat blood cancer patients with allogeneic HSCT without GvHD and toxicity.

Immune Reconstitution At Days 30 and 100 Following Allogeneic Stem Cell Transplant and Association with Subsequent Development of Chronic Graft-Versus-Host Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1949-1949
Author(s):  
Samantha M. Jaglowski ◽  
Sumithira Vasu ◽  
Susan Geyer ◽  
Anissa Bingman ◽  
Patrick Elder ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Cell Activation ◽  
Univariate Analysis ◽  
Subsequent Development ◽  
Cell Transplant ◽  
Over Time

Abstract Abstract 1949 Introduction: Chronic graft-versus-host disease (cGVHD) is the most common long-term complication of allogeneic stem cell transplant (allo-SCT), affecting 30–70% of patients who survive beyond the first 100 days. While there is evidence to support a role for activated B cells, the exact cause of cGVHD remains unknown. Thus, we evaluated the influence of lymphocyte reconstitution at days 30 and 100 following allo-SCT on subsequent development of cGVHD. Methods: An extensive immune reconstitution flow cytometric “immunome” assay was developed at The Ohio State University, allowing for monitoring of changes in cell activation markers, memory T cell status, Treg subsets, NK cell subsets and Th1 vs Th2 cell subsets. To evaluate the effect of immune reconstitution on development of cGVHD, we have correlated samples collected at days 30 and 100 following allo-SCT with an IRB-approved, clinical database of patients who have received an SCT. Day 30 samples were collected on 70 patients, 66 patients had day 100 samples, and 40 patients had both. Logistic regression was used to evaluate the influence of both absolute numbers and percentage of lymphocyte subsets on the subsequent development of cGVHD. Because so few subsets were associated at both d30 and d100, we evaluated the influence of change over time using a Wilcoxon rank sum test. Results: All patients received either a peripheral blood or bone marrow graft, and 62% had unrelated donors. The median age was 55, and the median time to development of cGVHD was 155 days (range 110–389). On univariate analysis for the d30 samples, increased odds of developing cGVHD were associated with increased absolute numbers of naïve CD4+ and CD8+ T cells (p=0.05 and 0.02, respectively), as well as CD3-/CD56+16+/CD117- NK cells (p=0.05). These were not associated with cGVHD on univariate analysis for the d100 samples, but CD4+/CD193+ (p=0.018) and CD4+/CD183+ (p=0.015) were significantly associated at that time point. A higher percentage of activated NK cells (p=0.002) at d30, as well as a higher percentage of CD3+/CD69+cells (p=0.04), appears negatively associated with subsequent development of cGVHD. Higher percentages of both activated and naïve CD4+ cells at d100 were associated with cGVHD (p=0.03–0.04). Additionally, higher percentages of CD4+/CD29+ (p=0.03), CD4+/CD193+ (p=0.016), and CD4+/CD183+ cells (p=0.04) were positively associated. A higher percentage of CD8+/CD27- (p=0.02), CD8+/CD29- (p=0.03), andCD27-/CDRO+ (p=0.045) cells appeared to have a negative association with cGVHD. Percent of CD4+/CD27+ cells was the only marker to have an association at both d30 and d100 (p=0.045 and 0.01 respectively). From d30 to d100, there were statistically significant larger decreases in the absolute number of CD8+/CD45RO- T cells (p<0.0001) and CD3-/CD56+16+/CD117- NK cells (p<0.0001) among patients who developed cGVHD. A larger decrease in the percentage of CD3-/CD56+16+/CD117- NK cells was seen, as well (p<0.0001). A larger increase in the percentages of CD19+/CD86+ B cells (p=0.023) and naïve CD4+ T cells were associated with cGVHD. cGVHD was also associated with an increase in both the number and percentage of CD4+/CD193+ cells (p=0.006 and 0.0001 respectively) over time, compared with a decrease among patients who did not develop cGVHD. Multivariate analysis is ongoing. Conclusion: Patients who developed cGVHD had a larger increase in CD4+ T cells and a smaller increase in CD8+ T cells compared with patients who did not develop cGVHD over time, suggesting a selective expansion of CD4+ T cells. Further, a significant decrease in NK cells and concomitant increase in percentages of activated B cells was noted. An increase in CD4+ cells is associated with an inflammatory phenotype, and a Th2-skewed proinflammatory response may contribute to B cell activation, which has previously been associated with cGVHD. The presence of a Th2-skewed phenotype is supported by the presence of increased CD4+/CD193+ cells among patients with cGVHD, as CCR3 is preferentially expressed on Th2 cells. While a Th2-skewed phenotype has been demonstrated in several mouse models of cGVHD, this has not been established in humans. Further analysis will be needed before conclusions can be reached, but routine use of the “immunome” and clinical correlation may allow for more insight into the pathogenesis of cGVHD in humans and contribute to identification of targets for therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

Activation of DR3 Signaling Expands Recipient Derived Regulatory T Cells and Enhances Donor Immune Reconstitution Derived from Allogeneic Hematopoietic Stem Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1087-1087
Author(s):  
Hidekazu Nishikii ◽  
Byung Su Kim ◽  
Antonio Pierini ◽  
Jeanette Baker ◽  
Dominik Schneidawind ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Hematopoietic Stem ◽  
Hsc Transplantation

Abstract CD4+ Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells which regulate the immune system, maintain the tolerance of self-antigens and enhance immune tolerance after transplantation. It was also reported that recipient derived Treg could provide immune privilege to allogeneic stem cells (HSC) after transplantation. However, the precise interaction with Treg and HSC has not been fully elucidated. In this study, we investigated the role of recipient derived Treg in the engraftment and immune reconstitution following transplantation of purified allogeneic HSC and the effectiveness of Treg expansion following activation of DR3 (Death receptor 3, also called as TNFRSF25) signaling in this model. 　We first tested the effect of Treg depletion using Foxp3-DTR mice in allogeneic HSC transplantation. In this system, FACS-sorted purified HSC (Lin-cKit+Sca1+ population) derived from WT-FVB mice (CD45.1+/H2kq+) were injected into lethally irradiated B6-Foxp3-DTR mice (CD45.2+/H2kb+) with or without pre-treatment of diphtheria toxin (DT). On day 0 and day 28 after transplantation decreased frequencies of Foxp3+ cells in residual recipient derived CD4+ T cells were observed in peripheral blood from the DT treated mice (P<0.001 on day 0, P<0.002 on day 28). Although total myeloid chimerism was comparable between control and DT-treated mice, the frequency of donor derived immune cells including CD4+ T cells (P<0.01 on day 56), CD8+ T cells (P<0.01 on day 56), and B220+ B cells (P<0.001 on day 56) was significantly decreased in DT-treated mice. These data suggested that recipient derived Treg play an important role in allogeneic immune reconstitution after transplantation. DR3 is a member of the TNF receptor superfamily and we previously reported the expansion of Treg by the activation of this signaling pathway (Kim et al, ASH abstract 2013). We next tested whether activation of DR3 signaling by its agonistic antibody would affect the donor immune reconstitution after allogeneic HSC transplantation. The frequencies of Foxp3+ cells in CD4+ T cells were significantly increased in thymus, spleen, peripheral blood, and bone marrow 4 days after antibody injection (P<0.01). Isolated Treg derived from antibody treated mice showed stronger suppressive function in the mixed lymphoid reaction compared with those from isotype antibody treated mice. The mice treated with antibody on day -4 were transplanted with purified allogeneic HSC on day 0. Antibody treated mice showed a higher frequency of donor derived CD4+ T cells (P<0.001 on day 28), CD8+ T cells (P<0.05 on day 28), and B220+ B cells (P<0.05 on day 28) in this allogeneic HSC transplantation model. In summary, our data suggest that recipient derived CD4+Foxp3+ Treg play an important role in donor immune reconstitution and the activation of DR3 signaling in recipient mice enhances donor immune reconstitution by expansion of recipient derived Treg. H.N and BS-K contributed equally to this work. Disclosures No relevant conflicts of interest to declare.

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