Inflammatory TH1 Cytokines in Target Tissues Promote the Recruitment of Alloreactive T Cells in Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2451-2451 ◽  
Author(s):  
Jeanette Baker ◽  
Andreas Beilhack ◽  
Lu-en Wai ◽  
Stephan Schulz ◽  
Carolin Kiesel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Cell Recruitment ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Effector Phase

Abstract Abstract 2451 Poster Board II-428 Hematopoietic cell transplantation (HCT) is a curative therapy for a variety of malignancies. HCT provides disease eradication through both the high-dose conditioning regimen and an allogeneic graft versus tumor effect (GVT), however graft-versus-host disease (GVHD) remains a major obstacle. In a murine aHCT model of bioluminescence imaging (BLI) we have previously demonstrated that acute GVHD can be separated to a GVHD initiation phase confined to secondary lymphoid organs and a subsequent GVHD effector phase in peripheral target tissues. It has been proposed that host conditioning may not only be crucial in the activation of alloreactive T cells but also determine acute GVHD organ manifestation in the effector phase. Here we wanted to investigate how the host conditioning regimen affects the host target tissues in terms of inflammatory cytokines and their role in donor T cell recruitment. We compared lethally irradiated (8Gy) vs. non-irradiated Balb/c wild type or Balb/c Rag-/-cGC-/- (H-2d) -DKO mice that received allogeneic luciferase+ FVB/N T cells (H-2q). Surprisingly, we did not observe marked differences in the donor T cell proliferation (BLI, CFSE), acquisition of activation markers (CD25, CD44, CD69) and homing receptors (a4b7, aEb7, P-selectin ligand, E-selecting ligand) in conditioned, non-conditioned Balb/c Rag-/-cGC-/-. Despite the upregulation of these homing receptors on donor T cells, infiltration of target tissues (intestinal tract, liver and skin) was significantly accelerated in conditioned and delayed in non-conditioned hosts. As T cell recruitment may have occurred as a result of alterations of the milieu inflammatory cytokines in GVHD target tissues, we compared the cytokine profile in conditioned vs. non-conditioned recipients. At days 3 and 6 after transplantation tissues were harvested and cytokines from the target tissues; liver, large bowel, small bowel, peripheral blood and a non target tissue: kidney were analyzed for a TH1/TH2/Th17a cytokines. At day 3 high levels of INF-γ and TNF were detected in the Balb/c WT conditioned host compared to the non-conditioned host in all target tissues (SB, LB, and liver) and most markedly in peripheral blood and the large bowel. More importantly the Balb/c Rag-/-cGC-/- conditioned host displayed about 5 times higher levels of both inflammatory cytokines compared to the non conditioned DKO hosts and to the Balb/c WT. Similar results with a lesser levels were observed both for IL-2 and IL17a. By day 6 similar results are seen but with a much reduced expression of the cytokines, indicating that the cytokine storm peak was maybe at day 3. In summary host conditioning is not a requirement for alloreactive T cell activation rather induced inflammatory cytokines such as TNF and INF-γ are the determinant factors for effector T cell recruitment to GVHD target tissues. JB and AB contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.

Predictive Markers for Acute Graft-Versus-Host Disease in the Peripheral Blood - Surface Receptor Profile Defines Alloreactive T Cells In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 622-622
Author(s):  
Andreas Beilhack ◽  
Robert Zeiser ◽  
Stephan Schulz ◽  
Janelle A. Olson ◽  
Ryosei Nishimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Target Organ ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Effector Phase ◽  
Selectin Ligand ◽  
Acute Graft

Abstract Acute graft-versus-host disease (aGVHD) still results in high morbidity and mortality in patients undergoing allogeneic hematopoietic cell transplantation (aHCT). Early diagnosis of aGVHD remains difficult and is made based on clinical symptoms and histological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestations. Therefore, it is important to develop predictive assays to identify patients at risk of developing aGVHD for improved disease prevention. Using bioluminescence imaging (BLI) we have recently demonstrated that aGVHD pathogenesis is tightly spatially and temporally regulated in a murine model across major histocompatibility barriers. Therefore, we asked whether insights in the timing of aGVHD initiation and effector phase could allow for the development of a diagnostic test whereby specific cell surface profiles can predict the onset of aGVHD. FVB/N (H-2q, Thy1.1+, 4x106) or C57Bl/6 (H-2b, Thy1.1+, 4x106) splenocytes plus bone marrow (BM) cells (5x106) were transplanted into conditioned (2x400rad) allogeneic Balb/c (H-2d, Thy1.2+) or syngeneic (2x450rad) C57Bl/6 (H-2b, Thy1.2+) recipients. Allogeneic recipients developed the first clinical signs of aGVHD starting at day+6 which progressed rapidly to animal death typically by day+14. However, BLI revealed that aGVHD target organ infiltration had already occurred days earlier. On day+3 after aHCT, dividing (BrdU+) donor derived allogeneic T cells (Thy1.1+) were still confined to the T cell areas in secondary lymphoid organs. Between day+3 and day+4 T cells appeared in the red pulp of the spleen, indicating likely entry into the blood circulation. Thereafter, increasing aGVHD target organ infiltration became apparent. These findings prompted us to analyze peripheral blood (PB) samples from allogeneic vs. syngeneic recipients (day+1 to +6). Until day+3 after aHCT, no significant PB T cell numbers were detectable. However, by day+4 we found a dramatic increase of PB T cells (mostly CD4+, by day+5 mostly CD8+) that were CD44hi and expressed the homing receptors α4β7 integrin, αEβ7 integrin, CCR9, E-selectin ligand, P-selectin ligand, CCR5, and CXCR3 in allogeneic recipients, but not in syngeneic or BM controls. These T cell populations could be verified as clonally expanded (CFSElo) donor-derived alloreactive T cell subsets (Thy1.1+). In summary, alloreactive T cells could be identified by the timed up-regulation of a panel of distinct homing receptors. Furthermore, the transition between aGVHD initiation and effector phase emerged as an early diagnostic window for the detection of alloreactive T cells in the peripheral blood days before aGVHD onset. Taken together, this approach could predict aGVHD in order to tailor immunosuppressive therapy for individual patients.

scholarly journals Signaling Through the Type 2 Cannabinoid Receptor Regulates the Severity of Acute and Chronic Graft versus Host Disease

Blood ◽  
2020 ◽  
Author(s):  
Cheng Yin Yuan ◽  
Vivian Zhou ◽  
Garrett Sauber ◽  
Todd M Stollenwerk ◽  
Richard Komorowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Acute Gvhd ◽  
Cannabinoid Receptor ◽  
Therapeutic Targeting ◽  
Host Disease ◽  
Graft Versus Host

Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R) which is expressed on nearly all immune cells and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells, or administration of a selective CB2R pharmacological antagonist, exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T cell alloreactivity. Using a novel CB2R-EGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions. Therapeutic targeting of the CB2R with the agonists, tetrahydrocannabinol (THC) and JWH-133, revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contribute to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and ERK phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase. These studies demonstrate that the CB2R plays a critical role in the regulation of GVHD and suggest that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.

scholarly journals Prevention of Graft-Versus-Host Disease in Mice Using a Suicide Gene Expressed in T Lymphocytes

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4636-4645 ◽  
Author(s):  
José L. Cohen ◽  
Olivier Boyer ◽  
Benoı̂t Salomon ◽  
Rosine Onclercq ◽  
Frédéric Charlotte ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Therapeutic Strategy ◽  
Suicide Gene ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Cell Pool ◽  
Ganciclovir Treatment

Abstract Alloreactive T cells present in a bone marrow transplant are responsible for graft-versus-host disease (GVHD), but their depletion is associated with impaired engraftment, immunosuppression, and loss of the graft-versus-leukemia effect. We developed a therapeutic strategy against GVHD based on the selective destruction of these alloreactive T cells, while preserving a competent T-cell pool of donor origin. We generated transgenic mice expressing in their T lymphocytes the Herpes simplex type 1 thymidine kinase (TK) suicide gene that allows the destruction of dividing T cells by a ganciclovir treatment. T cells expressing the TK transgene were used to generate GVHD in irradiated bone marrow grafted mice. We show that a short 7-day ganciclovir treatment, initiated at the time of bone marrow transplantation, efficiently prevented GVHD in mice receiving TK-expressing T cells. These mice were healthy and had a normal survival. They maintained a T-cell pool of donor origin that responded normally to in vitro stimulation with mitogens or third party alloantigens, but were tolerant to recipient alloantigens. Our experimental system provides the proof of concept for a therapeutic strategy of GVHD prevention using genetically engineered T cells.

Augmented Regulatory T Cell Response After Photochemical Treatment Alleviates Acute Graft-Versus-Host Disease and Improves Survival.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3740-3740
Author(s):  
Bindu Kanathezhath ◽  
Sandra K Larkin ◽  
Julika Kaplan ◽  
Mark C. Walters ◽  
Frans Kuypers
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Allogeneic Transplantation ◽  
Post Transplantation ◽  
Graft Versus Host ◽  
Cytokine Milieu ◽  
Th1 Cytokines

Abstract Abstract 3740 Graft-versus-Host disease (GVHD) causes significant morbidity and mortality after allogeneic transplantation. Regulatory T cells of both donor and host origin can limit GVHD. Acute GVHD early post transplantation is heralded by a cytokine storm induced by a dominant T helper type 1(Th1) response, which damages host tissues like skin, gut, liver and lungs. We hypothesized that co-transplantation of photochemically (S-59) treated T cells modulates T cell effecter subsets and their cytokine milieu, and thereby reduces acute GVHD. To this end, we transplanted whole bone marrow cells in a major histocompatibility complex (MHC) antigen mismatched murine model using marrow with T cells from C57BL/6J AKR (acute GVHD model), with and without S-59 treatment. We observed equivalent elevation of CD4+Th1 (IL-2 and IFN-g), cytotoxic CD8+ (FAS, IFN-g and TNF-a) and CD4+Th2 (IL-4, IL-5, IL-6, IL-13) cytokines in recipients of both groups during the first week after transplantation. While the Th1 cytokines persisted as long as 10 days after transplantation, there was a shift to a regulatory T cell (Treg) cytokine profile (Transforming growth factor b [TGF-b] and IL-10) in the group that received the S-59 treated T cells. TGF-b and IL-10 levels were higher in the peripheral blood and bone marrow of the study group compared to controls (table). This was accompanied by the appearance of FoxP3High CD4+ CD25+ Tregs in the spleen and CD4+ Th17 cytokine (IL-17) elevation in the thymic compartment of recipients that received S-59 treated T cells (mean-28.44pg/ml versus 1.45pg/ml, p=0.0059). In-vivo tracking of S-59 treated T cells demonstrated the disappearance of these cells in the peripheral blood, spleen, bone marrow and thymus by 48 hours after transplantation. Nonetheless, we noted that recipients of S-59 treated T cells had significantly less acute GVHD and better overall survival (p=0.0001). In summary, our experiments indicate that there is an initial dominance of inflammatory and CD4 Th1 cytokines immediately post transplantation. Co-transplantation of S-59 treated T cells shifts the effecter CD4 T cell profile to resemble a Treg phenotype. Despite the absence of circulating photochemically treated T cells, significant alterations in the recipient cytokine milieu persisted after transplantation. Thus, S-59 treated T cells appear to exert an important immunomodulatory effect to ameliorate GVHD and improve survival after MHC-mismatched allogeneic transplantation. Blood (pg/ml) Bone marrow (pg/ml) Thymus (pg/ml) TGF-b [S59] 8482.7 * 7062.1 2926.9 TGF-b [control] 1.1 301.55 46.5 IL-10 [S59] 419.0 ** 174.0 30.4 IL-10 [control] <1 82.1 33.44 ρ value- * 0.0001 ** 0.0006 Disclosures: No relevant conflicts of interest to declare.

CD19 CAR T Cells Maintain Efficacy in the Allogeneic Environment but Mediate Acute Graft-Versus-Host-Disease Only in the Presence CD19+ Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1115-1115
Author(s):  
Elad Jacoby ◽  
Haiying Qin ◽  
Yinmeng Yang ◽  
Christopher Daniel Chien ◽  
Terry J Fry
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Ifn Gamma ◽  
Graft Versus Host ◽  
Car T Cells ◽  
Car T

Abstract A significant portion of patients with relapsed acute lymphoblastic leukemia (ALL) who are eligible for treatment with chimeric-antigen-receptor (CAR) T cells have undergone a previous hematopoietic stem cell transplantation. We and others have previously demonstrated that the allogeneic environment, even in the presence mild graft-versus-host disease (GVHD), severely impairs tumor-directed T-cell immunity. To study the behavior of CAR cells in the allogeneic setting we chose a murine model of minor mismatched allogeneic T-cell depleted bone marrow transplantation (BMT) followed by CAR T (CD19-28-z) cell infusion in recipients bearing a murine B-precursor ALL model (positive for CD19). Importantly, the leukemia persists following myeloablative radiation thus mimicking post-transplant minimal residual disease. Donor-derived, post-transplant injection of CD19 CAR T cells eliminated residual leukemia in the syngeneic as well as the allogeneic settings. CD19 CAR T cells harvested from allogeneic recipients maintained in-vitro ability to produce IFN-gamma and degranulate in the presence of ALL ex vivo, at levels comparable to syngeneic CD19 CAR T cells. However, CAR T cells administered in the allogeneic environment had the potential to mediate severe acute GVHD with early mortality of recipients not typically seen in this minor mismatch model. This occurred across multiple T cell doses capable of clearing leukemia (0.3e6-5e6), in transduced CD19 CAR T cells generated from donors tolerized to allogeneic antigens, and when CD19 CAR T cell infusion was delayed following BMT. In-vivo tracking of transferred cells showed comparable expansion and persistence of the CD19 CAR T cells in the allogeneic and syngeneic environments. However, syngeneic CAR T cells tended to develop later into central memory T cells (CD62L+CD44+), whereas the profile of allogeneic cells was significantly skewed toward effector T cells (CD62L-CD44+). Remarkably, the process of CAR-driven acute GVHD in this minor mismatch model was only seen in the presence of leukemia, indicating a CAR-target interaction influences the induction of GVHD. Indeed, pro-inflammatory cytokines IFN-gamma and IL-6 were elevated only in the presence of both ALL and CAR T cells, whereas TNF alpha levels were undetectable in all instances. We are currently testing whether neutralization of cytokines can prevent GVHD in these models. Altogether, these data demonstrate efficacy of CD19 CAR to clear residual leukemia in an immunocompetent mouse model, and maintain initial cytotoxicity despite the potentially suppressive allogeneic environment. However, we demonstrated potential risks of allogeneic CAR T cells aggravating GVHD in the presence of residual leukemia, likely via cytokine-mediated manner. Clinically, as IL-6 was shown to be significant in cytokine release syndrome, this may represent a murine model to study potential interventions. Disclosures No relevant conflicts of interest to declare.

scholarly journals Interleukin-18 Regulates Acute Graft-Versus-Host Disease by Enhancing Fas-mediated Donor T Cell Apoptosis

2001 ◽  
Vol 194 (10) ◽  
pp. 1433-1440 ◽  
Author(s):  
Pavan Reddy ◽  
Takanori Teshima ◽  
Mark Kukuruga ◽  
Rainer Ordemann ◽  
Chen Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ ◽  
Acute Graft

Interleukin (IL)-18 is a recently discovered cytokine that modulates both T helper type 1 (Th1) and Th2 responses. IL-18 is elevated during acute graft-versus-host disease (GVHD). We investigated the role of IL-18 in this disorder using a well characterized murine bone marrow transplantation (BMT) model (B6 → B6D2F1). Surprisingly, blockade of IL-18 accelerated acute GVHD-related mortality. In contrast, administration of IL-18 reduced serum tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) levels, decreased intestinal histopathology, and resulted in significantly improved survival (75 vs. 15%, P &lt; 0.001). Administration of IL-18 attenuated early donor T cell expansion and was associated with increased Fas expression and greater apoptosis of donor T cells. The administration of IL-18 no longer protected BMT recipients from GVHD when Fas deficient (lpr) mice were used as donors. IL-18 also lost its ability to protect against acute GVHD when interferon (IFN)-γ knockout mice were used as donors. Together, these results demonstrate that IL-18 regulates acute GVHD by inducing enhanced Fas-mediated apoptosis of donor T cells early after BMT, and donor IFN-γ is critical for this protective effect.

T-Cell Transcriptome Analysis Reveals the Mechanisms Controlling Synergy Between Costimulation Blockade and mTOR Inhibition during Graft Versus Host Disease Prevention

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3824-3824
Author(s):  
Scott N. Furlan ◽  
Benjamin Watkins ◽  
Kelly Hanby ◽  
Aneesah P. Garrett ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Therapeutic Approach ◽  
Acute Gvhd ◽  
Costimulation Blockade ◽  
Mtor Inhibition ◽  
Free Survival ◽  
Graft Versus Host ◽  
Flow Cytometric

Abstract While novel therapeutics for graft versus host disease (GvHD) are desperately needed, new prevention and treatment strategies for this disease have been extremely slow to reach the clinic. One of the major barriers has been the historic lack of a powerful translational system capable of both (1) interrogating the clinical efficacy of novel approaches and (2) discovering the underlying mechanisms of GvHD prevention. Our lab has addressed this unmet need with the development of a non-human primate (NHP) model of GvHD, and the first therapeutic approach developed with the NHP model, costimulation blockade with CTLA4-Ig, is currently in clinical trials for GvHD prevention (Clinical Trials.gov #NCT01743131). While the first-in-disease trials of GvHD prevention add CTLA4-Ig to standard tacrolimus/methotrexate, previous work has suggested that mTOR inhibition with sirolimus is more pro-tolerogenic than calcineurin inhibition when paired with costimulation blockade. We have now addressed the possibility of pairing CTLA4-Ig with sirolimus to prevent GvHD in the NHP model, and have interrogated the outcomes using a systems-based approach. Our new experiments provide strong clinical, immunologic and trancriptomic evidence for potent synergy when CTLA4-Ig and sirolimus are combined for GvHD prevention. In this study, we determined the impact of the following treatment groups on GvHD after high-risk haplo-identical HSCT using T cell-replete peripheral blood stem cell transplantation: 1) no therapy (n=4) 2) CTLA4-Ig monotherapy (using the second generation CTLA4-Ig formulation, belatacept, n=3) 3) sirolimus monotherapy (n=4) 4) combination belatacept and sirolimus (n=3). To determine the relative impact of each therapeutic approach, we monitored clinical GvHD, GvHD-free survival, and flow cytometric signs of immune activation post-transplant. Moreover, to create a comprehensive molecular map of their impact on GvHD, we performed transcriptomic analysis, on CD3+/CD20- T cells that were purified on day +14 post-transplant and analyzed using the Affymetrix microarray platform. The synergistic impact of combined belatacept +sirolimus was evidenced through all analyses techniques: Thus, GvHD-free survival with belatacept + sirolimus was prolonged compared to all other groups (MST belatacept + sirolimus = 33d, p < 0.02 compared to MST for untreated controls (7.5d), belatacept monotherapy (9d, p < 0.03) and sirolimus monotherapy (12d) (Figure 1a). GvHD clinical scores mirrored the clinical survival (Figure 1b). In addition, canonical flow cytometric signs of CD8+ T cell activation (proliferation, measured by Ki-67, and excessive cytotoxicity measured by granzyme B overexpression) also mirrored the clinical synergy we measured with combined belatacept +sirolimus compared to all other groups (Figure 1c). Comparing the expression profile of T cells during acute GvHD in the four cohorts allowed examination of treatment synergy at an unprecedented level of molecular detail. Unsupervised analysis of transcriptomic signatures as a whole revealed clustering of principal component projections from belatacept + sirolimus to be strikingly similar to a large comparative healthy control cohort (n=28), underscoring the high degree of control alloreactivity with this regimen. Moreover, the comparison of differentially expressed genes from animals receiving belatacept + sirolimus revealed significant divergence from monotherapy with either belatacept or sirolimus, again underscoring the profound control of allo-activation that was observed with belatacept + sirolimus (Figure 2a). The mirror-image analysis provided additional support or this synergy, with transcriptional analysis of T cells from belatacept + sirolimus-treated animals most dissimilar from the transcriptome of unprophylaxed GvHD (Figure 2b). Those genes for which expression was significantly normalized by combination therapy showed pathway enrichment prominently in T cell effector function (prominently including granzyme signaling – Figure 2c), cytokine networks (prominently IL2, IL12 and IL-18 – Figure 2d), as well as in proliferation and cell cycle pathways (Figure 2e). These data reveal a treatment synergy between T cell costimulation blockade with CTLA-4-Ig and mTOR inhibition and suggest that this combination of therapy will be useful for acute GvHD immunoprophylaxis in humans. Disclosures No relevant conflicts of interest to declare.

scholarly journals Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3308-3313 ◽  
Author(s):  
Steven Z. Pavletic ◽  
Shelly L. Carter ◽  
Nancy A. Kernan ◽  
Jean Henslee-Downey ◽  
Adam M. Mendizabal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Conditioning Regimen ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact

AbstractDonor-derived T cells have been proposed to play a role in pathogenesis of chronic graft-versus-host disease (cGVHD). The impact of ex vivo T-cell depletion (TCD) on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation-based myeloablative conditioning regimen. GVHD prophylaxis included TCD plus cyclosporine (CSA) or unmodified grafts with CSA plus methotrexate (M/C). Median recipient age was 31.2 years (range, 0.5-55.6 years); median follow-up time since randomization was 4.2 years. The mean number of T cells infused was 1 log lower on the TCD arm. The incidence of cGVHD at 2 years was similar between the TCD and M/C arms, 29% versus 34% (P = .27), respectively. Survival at 3 years from diagnosis of cGVHD was also similar, (TCD 51% versus M/C 58%; P = .29). The proportion of patients with cGVHD who discontinued immunosuppression at 5 years was not different (TCD 72% versus M/C 63%; P = .27), and incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed cGVHD.

scholarly journals Targeting T Cell Bioenergetics by Modulating P-Glycoprotein Selectively Depletes Alloreactive T Cells To Prevent Graft-versus-Host Disease

2016 ◽  
Vol 197 (5) ◽  
pp. 1631-1641 ◽  
Author(s):  
Zachariah A. McIver ◽  
Jason M. Grayson ◽  
Benjamin N. Coe ◽  
Jacqueline E. Hill ◽  
Gregory A. Schamerhorn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
P Glycoprotein

scholarly journals Tolerogenic anti-IL-2 mAb prevents graft-versus-host disease while preserving strong graft-versus-leukemia activity

Blood ◽  
2021 ◽  
Author(s):  
Qingxiao Song ◽  
Xiaoning Wang ◽  
Xiwei Wu ◽  
Hanjun Qin ◽  
Yingfei Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Lymphoid Tissues ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gm Csf ◽  
Graft Versus Leukemia ◽  
Donor T Cells

Donor T cells mediate both graft-versus-leukemia (GVL) activity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (Allo-HCT). Development of methods that preserve GVL activity while preventing GVHD remains a long-sought goal. Tolerogenic anti-IL-2 monoclonal antibody (mAb) (JES6-1) forms anti-IL-2/IL-2 complexes that block IL-2 binding to IL-2Rb and IL-2Rg on Tcon cells that have low expression of IL-2Rα. Here we show that administration of JES6 early after Allo-HCT in mice markedly attenuates acute GVHD while preserving GVL activity that is dramatically stronger than observed with tacrolimus (TAC) treatment. The anti-IL-2 treatment down-regulated activation of IL-2-Stat5 pathway and reduced production of GM-CSF. In GVHD target tissues, enhanced T cell PD-1 interaction with tissue-PD-L1 led to reduced activation of AKT-mTOR pathway and increased expression of Eomes and Blimp-1, increased T cell anergy/exhaustion, expansion of Foxp3-IL-10-producing Tr1 cells, and depletion of GM-CSF-producing Th1/Tc1 cells. In recipient lymphoid tissues, lack of donor T cell PD-1 interaction with tissue-PD-L1 preserved donor PD-1+TCF-1+Ly108+CD8+ T memory progenitors (Tmp) and functional effectors that have strong GVL activity. Anti-IL-2 and TAC treatments have qualitatively distinct effects on donor T cells in the lymphoid tissues, and CD8+ Tmp cells are enriched with the anti-IL-2 treatment compared to TAC treatment. We conclude that administration of tolerogenic anti-IL-2 mAb early after Allo-HCT represents a novel approach for preventing acute GVHD while preserving GVL activity.

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