Treg Induced Impairment of DC Function and Its Impact on GvH Reactions

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3815-3815
Author(s):  
Mavin Emily ◽  
Lindsay Nicholson ◽  
Rafez Ahmed ◽  
Matthew Collin ◽  
Anne Dickinson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tissue Damage ◽  
Conflicts Of Interest ◽  
Cd8 T Cell ◽  
Target Tissue ◽  
T Cell Priming ◽  
The Impact

Abstract Promising results from murine models and early stage clinical trials have shown that adoptive transfer of regulatory T cells (Treg) prevents graft-versus-host disease (GvHD). However, the primary target of Treg mediated protection against GvHD is yet to be fully defined. We have previously shown that the presence of Treg during effector T cell priming is able to ameliorate cutaneous GvH reactions in vitro by blocking effector cell migration. This has led to the hypothesis that Treg modulation of dendritic cells (DC) could be a key mechanism by which Treg exert their protective role in GvHD. DC are fundamental for the initiation of allo-reactive immune responses and are critical in GvHD pathogenesis. We investigated the effect of Treg on the phenotypic profile and allo-reactive functions of DCs. Furthermore, the impact of Treg treatment on the ability of DCs to induce GvH target tissue damage was examined for the first time using an in vitro human GvHD skin explant model. Immature, mature and Treg treated DCs were generated from immuno-magnetic isolated monocytes (im-DC, mat-DC and Treg-DC respectively). The three moDC populations were generated using the well-established 6 day culture with GM-CSF and IL-4 followed by 24 hour LPS maturation. Treg were added on day 3 of moDC culture. Im-DC, mat-DC and Treg-DC were harvested on day 7 and tested in parallel as stated below. Prior to functional assays Treg-moDC were isolated by FACS sorting via FSC/SSC/CD3neg gating to remove Treg present in the co-culture. Our results revealed that Treg-DC displayed a semi-mature phenotype with CD83, CD80 and CD86 expression significantly lower than mat-moDC (p<0.005) but significantly higher than im-moDC (P<0.05) whilst HLA-DR levels were comparable to mat-moDC but significantly higher than imDC (p<0.005). Treg-DC also expressed CCR7 comparable to that of im-DC but markedly higher than mat-DC (p=0.052). Distinct morphology of Treg-DC, defined by Giemsa staining, corroborated their semi-mature status. Data from FITC-dextran uptake showed a significant reduction in antigen-capture capacity of Treg treated im-DC compared to untreated im-DC (p=0.047). The Treg mediated functional impairment of DCs was also associated with significantly higher expression of LAP-TGFβ1 on Treg-DC when compared to that of mat-DC (P<0.05). Treg-DC were also markedly defective in stimulating activation and proliferation of allo-reactive CD8 T cells, detected by CD25 expression and CFSE dilution respectively (p=0.009, p=0.046). Interestingly the presence of Treg throughout the entire allo-response induction resulted in a more potent reduction in activation and proliferation than when only the DC were treated with Treg (p=0.009, p=0.0085). Furthermore, allo-reactive CD8 T cells primed with Treg treated moDC were less able to mediate cutaneous GvH tissue damage (Figure 1). In conclusion, attenuation of DC signature and function is key for Treg mediated protection against GvHD. However, isolated DC modulation by Treg was less effective in suppressing CD8 T cell allo-responses compared to the continued presence of Treg during the CD8 T cell priming, activation and proliferation, suggesting that Treg exert most effective function via multidimensional modulation on the DC, T cells and DC-T cell interactions simultaneously. Figure 1. Skin histopathology induced by CD8 T cells primed with im-DC, mat-DC and Treg-DC Figure 1. Skin histopathology induced by CD8 T cells primed with im-DC, mat-DC and Treg-DC Disclosures No relevant conflicts of interest to declare.

MLL Histone Methyltransferase Restrains Effector Differentiation and PD-1 Expression in Human CD8+ T Cells While Promoting Their Proliferation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 863-863
Author(s):  
Janaki Purushe ◽  
Hongxin Sun ◽  
Shan He ◽  
Yali Dou ◽  
Yi Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Conflicts Of Interest ◽  
Flow Cytometric Analysis ◽  
Specific Effect ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Ifn Γ ◽  
The Impact

Abstract Adoptive cellular therapy (ACT) for cancer requires amplification and persistence of tumor-specific T cells. To completely eliminate malignant tumor cells, infused tumor-reactive T cells must retain the capacity to expand over weeks and months in order to produce sufficient effector cells. However, T-cell potency can be blunted by excessive differentiation and upregulation of PD-1, which mediates exhaustion and impairs their proliferative capacity. Histone methylation is thought to be central in directing transcriptional programs important for effector proliferation, survival and differentiation; however, the epigenetic regulator(s) of this process are not well characterized. We report that the histone methyltransferases Mixed Lineage Leukemia 1 (MLL1) and MLL4, which catalyze trimethylation of histone H3 at lysine 4 (H3K4me3), play important roles in restraining effector differentiation and promoting proliferation of activated human CD8+ T cells. Upon T cell receptor (TCR) activation, human CD8+ T cells upregulated MLL1 and MLL4, however, down-regulated the global level of H3K4me3. To assess the specific effect of MLL1 in CD8+ T cell differentiation, we produced lentivirus encoding short hairpin RNA (shRNA) specific to MLL1 or MLL4. Knockdown of either protein increased the frequency of IFN-γ-producing cells by 50% to 100%, with silencing of MLL1 having the more potent effect. Pharmacological inhibition with MI-2-2, which simultaneously inhibits the menin-MLL1 and menin-MLL4 interactions, increased the frequency of IFN-γ + CD8+ T cells three-fold and reduced cell proliferation from 94% to 64%. Using a second MLL1 inhibitor MM-401, which affects MLL1 specifically, we confirmed that inhibiting MLL1 resulted in a two-to-four-fold increase in the expression of numerous effector molecule transcripts, including IFNG, TNFA, PRF1, FASL and GZMB. Our results suggest that while both MLL1 and MLL4 are important for proliferation of activated CD8+ T cells, MLL1 potently restrains effector differentiation. T-BET and EOMES are two transcription factors critical for mediating effector differentiation. We found that inhibition of MLL1 in cultured, TCR-activated CD8+ T cells using either MI-2-2 or MM-401 led to a significant increase in expression of EOMES, but had no significant effect on T-BET expression. Flow cytometric analysis showed that silencing MLL1 also increased the expression of EOMES protein in activated CD8+ T cells. Interestingly, MLL1 knockdown impaired subsequent persistence of ex vivo expanding CD8+ T cells, which was associated with a substantial increase of CD45RO+CCR7- short-lived effector CD8+ T cells. Remarkably, knockdown of MLL1 in proliferating CD8+ T cells led to their upregulation of PD-1. Taken together, these data suggest that MLL1 may play an important role in restraining precocious effector differentiation and exhuastion in CD8+ T cells. Future studies will investigating the impact of both MLL1 and MLL4 in regulating the CAR CD8+ T cell response in vivo and in vitro. Results from these experiments will allow us to identify epigenetic mechanisms that regulate the generation and persistence of antitumor effector and memory CD8+ T cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals A new in vitro model of polymyositis reveals CD8+ T cell invasion into muscle cells and its cytotoxic role

Rheumatology ◽  
2019 ◽  
Vol 59 (1) ◽  
pp. 224-232
Author(s):  
Mari Kamiya ◽  
Fumitaka Mizoguchi ◽  
Akito Takamura ◽  
Naoki Kimura ◽  
Kimito Kawahata ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Muscle Injury ◽  
In Vitro Model ◽  
Muscle Cells ◽  
Cd8 T Cell ◽  
Class I ◽  
Vitro Model

Abstract Objectives The hallmark histopathology of PM is the presence of CD8+ T cells in the non-necrotic muscle cells. The aim of this study was to clarify the pathological significance of CD8+ T cells in muscle cells. Methods C2C12 cells were transduced retrovirally with the genes encoding MHC class I (H2Kb) and SIINFEKL peptide derived from ovalbumin (OVA), and then differentiated to myotubes (H2KbOVA-myotubes). H2KbOVA-myotubes were co-cultured with OT-I CD8+ T cells derived from OVA-specific class I restricted T cell receptor transgenic mice as an in vitro model of PM to examine whether the CD8+ T cells invade into the myotubes and if the myotubes with the invasion are more prone to die than those without. Muscle biopsy samples from patients with PM were examined for the presence of CD8+ T cells in muscle cells. The clinical profiles were compared between the patients with and without CD8+ T cells in muscle cells. Results Analysis of the in vitro model of PM with confocal microscopy demonstrated the invasion of OT-I CD8+ T cells into H2KbOVA-myotubes. Transmission electron microscopic analysis revealed an electron-lucent area between the invaded CD8+ T cell and the cytoplasm of H2KbOVA-myotubes. The myotubes invaded with OT-I CD8+ T cells died earlier than the uninvaded myotubes. The level of serum creatinine kinase was higher in patients with CD8+ T cells in muscle cells than those without these cells. Conclusion CD8+ T cells invade into muscle cells and contribute to muscle injury in PM. Our in vitro model of PM is useful to examine the mechanisms underlying muscle injury induced by CD8+ T cells.

BK Polyomavirus–Specific CD8 T-Cell Expansion In Vitro Using 27mer Peptide Antigens for Developing Adoptive T-Cell Transfer and Vaccination

2020 ◽  
Author(s):  
Maud Wilhelm ◽  
Amandeep Kaur ◽  
Marion Wernli ◽  
Hans H Hirsch
Keyword(s):  
T Cells ◽  
T Cell ◽  
Kidney Transplant ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Bk Polyomavirus

Abstract Background BK polyomavirus (BKPyV) remains a significant cause of premature kidney transplant failure. In the absence of effective antivirals, current treatments rely on reducing immunosuppression to regain immune control over BKPyV replication. Increasing BKPyV-specific CD8 T cells correlate with clearance of BKPyV DNAemia in kidney transplant patients. We characterized a novel approach for expanding BKPyV-specific CD8 T cells in vitro using 27mer-long synthetic BKPyV peptides, different types of antigen-presenting cells, and CD4 T cells. Methods Langerhans cells and immature or mature monocyte-derived dendritic cells (Mo-DCs) were generated from peripheral blood mononuclear cells of healthy blood donors, pulsed with synthetic peptide pools consisting of 36 overlapping 27mers (27mP) or 180 15mers (15mP). BKPyV-specific CD8 T-cell responses were assessed by cytokine release assays using 15mP or immunodominant 9mers. Results BKPyV-specific CD8 T cells expanded using 27mP and required mature Mo-DCs (P = .0312) and CD4 T cells (P = .0156) for highest responses. The resulting BKPyV-specific CD8 T cells proliferated, secreted multiple cytokines including interferon γ and tumor necrosis factor α, and were functional (CD107a+/PD1–) and cytotoxic. Conclusions Synthetic 27mP permit expanding BKPyV-specific CD8 T-cell responses when pulsing mature Mo-DCs in presence of CD4 T cells, suggesting novel and safe approaches to vaccination and adoptive T-cell therapies for patients before and after kidney transplantation.

scholarly journals IL4I1 Accelerates the Expansion of Effector CD8+ T Cells at the Expense of Memory Precursors by Increasing the Threshold of T-Cell Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Marie-Line Puiffe ◽  
Aurélie Dupont ◽  
Nouhoum Sako ◽  
Jérôme Gatineau ◽  
José L. Cohen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cell Clone ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Clone

IL4I1 is an immunoregulatory enzyme that inhibits CD8 T-cell proliferation in vitro and in the tumoral context. Here, we dissected the effect of IL4I1 on CD8 T-cell priming by studying the differentiation of a transgenic CD8 T-cell clone and the endogenous repertoire in a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection. Unexpectedly, we show that IL4I1 accelerates the expansion of functional effector CD8 T cells during the first several days after infection and increases the average affinity of the elicited repertoire, supporting more efficient LCMV clearance in WT mice than IL4I1-deficient mice. Conversely, IL4I1 restrains the differentiation of CD8 T-cells into long-lived memory precursors and favors the memory response to the most immunodominant peptides. IL4I1 expression does not affect the phenotype or antigen-presenting functions of dendritic cells (DCs), but directly reduces the stability of T-DC immune synapses in vitro, thus dampening T-cell activation. Overall, our results support a model in which IL4I1 increases the threshold of T-cell activation, indirectly promoting the priming of high-affinity clones while limiting memory T-cell differentiation.

scholarly journals Phenotypic and Functional Separation of Memory and Effector Human CD8+ T Cells

1997 ◽  
Vol 186 (9) ◽  
pp. 1407-1418 ◽  
Author(s):  
Dörte Hamann ◽  
Paul A. Baars ◽  
Martin H.G. Rep ◽  
Berend Hooibrink ◽  
Susana R. Kerkhof-Garde ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Fas Ligand ◽  
Cytotoxic T Lymphocyte ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Cytolytic Activity ◽  
T Cell Subset

Human CD8+ memory- and effector-type T cells are poorly defined. We show here that, next to a naive compartment, two discrete primed subpopulations can be found within the circulating human CD8+ T cell subset. First, CD45RA−CD45R0+ cells are reminiscent of memory-type T cells in that they express elevated levels of CD95 (Fas) and the integrin family members CD11a, CD18, CD29, CD49d, and CD49e, compared to naive CD8+ T cells, and are able to secrete not only interleukin (IL) 2 but also interferon γ, tumor necrosis factor α, and IL-4. This subset does not exert cytolytic activity without prior in vitro stimulation but does contain virus-specific cytotoxic T lymphocyte (CTL) precursors. A second primed population is characterized by CD45RA expression with concomitant absence of expression of the costimulatory molecules CD27 and CD28. The CD8+CD45RA+CD27− population contains T cells expressing high levels of CD11a, CD11b, CD18, and CD49d, whereas CD62L (L-selectin) is not expressed. These T cells do not secrete IL-2 or -4 but can produce IFN-γ and TNF-α. In accordance with this finding, cells contained within this subpopulation depend for proliferation on exogenous growth factors such as IL-2 and -15. Interestingly, CD8+CD45RA+CD27− cells parallel effector CTLs, as they abundantly express Fas-ligand mRNA, contain perforin and granzyme B, and have high cytolytic activity without in vitro prestimulation. Based on both phenotypic and functional properties, we conclude that memory- and effector-type T cells can be separated as distinct entities within the human CD8+ T cell subset.

scholarly journals 4-1BB co-stimulation enhances human CD8+ T cell priming by augmenting the proliferation and survival of effector CD8+ T cells

2002 ◽  
Vol 14 (10) ◽  
pp. 1155-1167 ◽  
Author(s):  
D. Laderach ◽  
M. Movassagh ◽  
A. Johnson ◽  
R. S. Mittler ◽  
A. Galy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Priming

scholarly journals The differential production of cytokines by human Langerhans cells and dermal CD14+ DCs controls CTL priming

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5742-5749 ◽  
Author(s):  
Jacques Banchereau ◽  
LuAnn Thompson-Snipes ◽  
Sandra Zurawski ◽  
Jean-Philippe Blanck ◽  
Yanying Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Langerhans Cells ◽  
Expression Profiles ◽  
Cd8 T Cell ◽  
Inhibitory Effect ◽  
Effector Memory ◽  
Functional Difference ◽  
T Cell Priming

Abstract We recently reported that human epidermal Langerhans cells (LCs) are more efficient than dermal CD14+ DCs at priming naive CD8+ T cells into potent CTLs. We hypothesized that distinctive dendritic cell (DC) cytokine expression profiles (ie, IL-15 produced by LCs and IL-10 expressed by dermal CD14+ DCs) might explain the observed functional difference. Blocking IL-15 during CD8+ T-cell priming reduced T-cell proliferation by ∼ 50%. These IL-15–deprived CD8+ T cells did not acquire the phenotype of effector memory cells. They secreted less IL-2 and IFN-γ and expressed only low amounts of CD107a, granzymes and perforin, and reduced levels of the antiapoptotic protein Bcl-2. Confocal microscopy analysis showed that IL-15 is localized at the immunologic synapse of LCs and naive CD8+ T cells. Conversely, blocking IL-10 during cocultures of dermal CD14+ DCs and naive CD8+ T cells enhanced the generation of effector CTLs, whereas addition of IL-10 to cultures of LCs and naive CD8+ T cells inhibited their induction. TGF-β1 that is transcribed by dermal CD14+ DCs further enhanced the inhibitory effect of IL-10. Thus, the respective production of IL-15 and IL-10 explains the contrasting effects of LCs and dermal CD14+ DCs on CD8+ T-cell priming.

scholarly journals Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis

2017 ◽  
Vol 214 (6) ◽  
pp. 1593-1606 ◽  
Author(s):  
Hossam A. Abdelsamed ◽  
Ardiana Moustaki ◽  
Yiping Fan ◽  
Pranay Dogra ◽  
Hazem E. Ghoneim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Human Memory ◽  
Memory Cd8 T Cells ◽  
Memory Cd8 T Cell ◽  
Cell Effector

Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell–mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (TEM), and longer-lived central memory (TCM) and stem cell memory (TSCM) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7– and IL-15–mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of TCM and TSCM memory cells resulted in phenotypic conversion into TEM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired TEM-associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells.

AAV-2 Capsid-Specific CD8+ T Cells Limit the Duration of Gene Therapy in Humans and Cross-React with AAV-8 Capsid.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 455-455 ◽  
Author(s):  
Federico Mingozzi ◽  
Marcela V. Maus ◽  
Denise E. Sabatino ◽  
Daniel J. Hui ◽  
John E.J. Rasko ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Transgene Expression ◽  
Cd8 T Cell ◽  
Target Cells

Abstract Efforts to establish an adeno-associated viral (AAV) vector-mediated gene therapy for the treatment of hemophilia B have been hindered by an immune response to the viral capsid antigen. Preclinical studies in small and large animal models of the disease showed long-term factor IX (F.IX) transgene expression and correction of the phenotype. However, in a recent phase I/II clinical trial in humans (Manno et al., Nat. Med. 2006), after hepatic gene transfer with an AAV-2 vector expressing human F.IX transgene, expression lasted for only a few weeks, declining to baseline concurrently with a peak in liver enzymes. We hypothesized that T cells directed towards AAV capsid antigens displayed by transduced hepatocytes were activated and these mediated destruction of the transduced hepatocytes, thereby causing loss of transgene expression and a transient transaminitis. Peripheral blood mononuclear cells isolated from AAV-infused subjects were stained with an AAV capsid-specific MHC class I pentamer either directly or after in vitro expansion. Two weeks after vector infusion 0.14% of circulating CD8+ T cells were capsid-specific on direct staining, and five weeks after infusion the capsid-specific population had expanded to 0.5% of the circulating CD8+ T cells, indicating proliferation of this T cell subset. By 20 weeks after vector infusion, the capsid-specific CD8+ T cell population had contracted to the level seen at 2 weeks. The expansion and contraction of this capsid-specific CD8+ T cell population paralleled the rise and fall of serum transaminases in the subject observed. Subsequent ex vivo studies of PBMC showed the presence of a readily expandable pool of capsid-specific CD8+ T cells up to 2.5 years post vector-infusion. Similarly, we were able to expand AAV-specific CD8+ T cells from peripheral blood of normal donors, suggesting the existence of a T cell memory pool. Expanded CD8+ T cells were functional as evidenced by specific lysis of HLA-matched target cells and by IFN-γsecretion in response to AAV epitopes. It has been argued that potentially harmful immune responses could be avoided by switching AAV serotypes, however, capsid protein sequences are highly conserved among different serotypes, as are some immunodominant epitopes that we identified. Indeed, we demonstrated that capsid-specific CD8+ T cells from AAV-infused hemophilic subjects functionally cross-react with AAV-8. Moreover, cells expanded from normal donors with AAV-2 vector capsids proliferated upon culture with AAV-8 capsids, demonstrating that both vectors could be processed appropriately in vitro to present the epitopic peptide to capsid-specific T cells. This suggests that AAV-2-specific memory CD8+ T cells normally present in humans likely would expand upon exposure to AAV-8 capsid epitopes. We conclude that the use of immunomodulatory therapy may be a better approach to achieving durable transgene expression in the setting of AAV-mediated gene therapy.

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