scholarly journals Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

2011 ◽  
Vol 208 (5) ◽  
pp. 1069-1082 ◽  
Author(s):  
Daigo Hashimoto ◽  
Andrew Chow ◽  
Melanie Greter ◽  
Yvonne Saenger ◽  
Wing-Hong Kwan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Expansion ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Host Macrophage

Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.

scholarly journals Donor-Derived CD4+ T Cells and Human Herpesvirus 6B Detection After Allogeneic Hematopoietic Cell Transplantation

2020 ◽  
Author(s):  
Derek J Hanson ◽  
Hu Xie ◽  
Danielle M Zerr ◽  
Wendy M Leisenring ◽  
Keith R Jerome ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cd4 T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Mononuclear Cells ◽  
Human Herpesvirus ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Peripheral Blood Mononuclear

Abstract We sought to determine whether donor-derived human herpesvirus (HHV) 6B–specific CD4+ T-cell abundance is correlated with HHV-6B detection after allogeneic hematopoietic cell transplantation. We identified 33 patients who received HLA-matched, non–T-cell–depleted, myeloablative allogeneic hematopoietic cell transplantation and underwent weekly plasma polymerase chain reaction testing for HHV-6B for 100 days thereafter. We tested donor peripheral blood mononuclear cells for HHV-6B–specific CD4+ T cells. Patients with HHV-6B detection above the median peak viral load (200 copies/mL) received approximately 10-fold fewer donor-derived total or HHV-6B–specific CD4+ T cells than those with peak HHV-6B detection at ≤200 copies/mL or with no HHV-6B detection. These data suggest the importance of donor-derived immunity for controlling HHV-6B reactivation.

Increased apoptosis of peripheral blood T cells following allogeneic hematopoietic cell transplantation

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3832-3839 ◽  
Author(s):  
Ming-Tseh Lin ◽  
Li-Hui Tseng ◽  
Haydar Frangoul ◽  
Ted Gooley ◽  
Ji Pei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Apoptosis ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Cd4 T Cell ◽  
Spontaneous Apoptosis ◽  
T Cell Apoptosis

Lymphopenia and immune deficiency are significant problems following allogeneic hematopoietic cell transplantation (HCT). It is largely assumed that delayed immune reconstruction is due to a profound decrease in thymus-dependent lymphopoiesis, especially in older patients, but apoptosis is also known to play a significant role in lymphocyte homeostasis. Peripheral T cells from patients who received HCT were studied for evidence of increased cell death. Spontaneous apoptosis was measured in CD3+ T cells following a 24-hour incubation using 7-amino-actinomycin D in conjunction with the dual staining of cell surface antigens. Apoptosis was significantly greater among CD3+ T cells taken from patients 19-23 days after transplantation (30.4% ± 12.5%,P < .05), and 1 year after transplantation (9.7% ± 2.8%, P < .05) compared with healthy controls (4.0% ± 1.5%). Increased apoptosis occurred preferentially in HLA (human leukocyte antigen)-DR positive cells and in both CD3+/CD4+ and CD3+/CD8+ T-cell subsets, while CD56+/CD3− natural killer cells were relatively resistant to apoptosis. The extent of CD4+T-cell apoptosis was greater in patients with grade II-IV acute graft-versus-host disease (GVHD) (33.9% ± 11.3%) compared with grade 0-I GVHD (14.6 ± 6.5%, P < .05). T-cell apoptosis was also greater in patients who received transplantations from HLA-mismatched donors (39.5% ± 10.4%,P < .05) or HLA-matched unrelated donors (32.1% ± 11.4%, P < .05) compared with patients who received transplantations from HLA-identical siblings (19.6% ± 6.7%). The intensity of apoptosis among CD4+ T cells was significantly correlated with a lower CD4+ T-cell count. Together, these observations suggest that activation of T cells in vivo, presumably by alloantigens, predisposes the cells to spontaneous apoptosis, and this phenomenon is associated with lymphopenia. Activation-induced T-cell apoptosis may contribute to delayed immune reconstitution following HCT.

scholarly journals Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK–modified donor T cells after allogeneic hematopoietic cell transplantation

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2294-2302 ◽  
Author(s):  
Carolina Berger ◽  
Mary E. Flowers ◽  
Edus H. Warren ◽  
Stanley R. Riddell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
T Cell Responses ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Cell Responses ◽  
Donor T Cells

AbstractThe introduction of an inducible suicide gene such as the herpes simplex virus thymidine kinase (HSV-TK) might allow exploitation of the antitumor activity of donor T cells after allogeneic hematopoietic cell transplantation (HCT) without graft versus host disease. However, HSV-TK is foreign, and immune responses to gene-modified T cells could lead to their premature elimination. We show that after the infusion of HSV-TK–modified donor T cells to HCT recipients, CD8+ and CD4+ T-cell responses to HSV-TK are rapidly induced and coincide with the disappearance of transferred cells. Cytokine flow cytometry using an overlapping panel of HSV-TK peptides allowed rapid detection and quantitation of HSV-TK–specific T cells in the blood and identified multiple immunogenic epitopes. Repeated infusion of modified T cells boosted the induced HSV-TK–specific T cells, which persisted as memory cells. These studies demonstrate the need for nonimmunogenic suicide genes and identify a strategy for detection of CD4+ and CD8+ T-cell responses to transgene products that should be generally applicable to monitoring patients on gene therapy trials. The potency of gene-modified T cells to elicit robust and durable immune responses imply this approach might be used for vaccination to elicit T-cell responses to viral or tumor antigens.

scholarly journals An Unconventional View of T Cell Reconstitution After Allogeneic Hematopoietic Cell Transplantation

2021 ◽  
Vol 10 ◽  
Author(s):  
Hana Andrlová ◽  
Marcel R. M. van den Brink ◽  
Kate A. Markey
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Intestinal Microbiome ◽  
Post Transplantation ◽  
Curative Intent

Allogeneic hematopoietic cell transplantation (allo-HCT) is performed as curative-intent therapy for hematologic malignancies and non-malignant hematologic, immunological and metabolic disorders, however, its broader implementation is limited by high rates of transplantation-related complications and a 2-year mortality that approaches 50%. Robust reconstitution of a functioning innate and adaptive immune system is a critical contributor to good long-term patient outcomes, primarily to prevent and overcome post-transplantation infectious complications and ensure adequate graft-versus-leukemia effects. There is increasing evidence that unconventional T cells may have an important immunomodulatory role after allo-HCT, which may be at least partially dependent on the post-transplantation intestinal microbiome. Here we discuss the role of immune reconstitution in allo-HCT outcome, focusing on unconventional T cells, specifically mucosal-associated invariant T (MAIT) cells, γδ (gd) T cells, and invariant NK T (iNKT) cells. We provide an overview of the mechanistic preclinical and associative clinical studies that have been performed. We also discuss the emerging role of the intestinal microbiome with regard to hematopoietic function and overall immune reconstitution.

scholarly journals Encouraging Survival and High Rates of Toxicity: Allogeneic Hematopoietic Cell Transplantation after Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy in Aggressive Lymphoma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 910-910
Author(s):  
Shalev Fried ◽  
Ivetta Danylesko ◽  
Ronit Yerushalmi ◽  
Noga Shem-Tov ◽  
Roni Shouval ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Aggressive Lymphoma ◽  
T Cell Therapy ◽  
Car T

Abstract Background Approximately 60% of patients with aggressive large B-cell lymphoma (ALBCL) treated with anti-CD19 chimeric antigen receptor T-cell (CAR T) will ultimately progress or relapse. Allogeneic hematopoietic cell transplantation (Allo-HCT) is a potentially curative treatment for lymphoma patients who relapse after CAR T-cell therapy. However, the efficacy and toxicity profile of allo-HCT following CAR T in aggressive lymphoma patients are not well defined. Herein, we report our experience. Methods and patients A total of 29 adult patients (median age 45 years [IQR 40-55]) who received allo-HCT for ALBCL between 2017 to 2021 were included. All patients were previously treated with anti-CD19 CAR T-cell (academic CD28-costimulatory domain product [n=23, 79%]; tisagenlecleucel [n=6, 21%]). Twenty-five (86%) and 4 (14%) had a diagnosis of DLBCL and PMBCL, respectively. Median number of previous therapies before CAR T was 3 (IQR 2-4). Eight (28%) patients underwent a previous autologous HCT. No patient underwent a previous allo-HCT. Median hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was 3 (IQR 2-3). Six (21%) patients had a Karnofsky performance status ≤ 80%. Allo-HCT was performed at a median of 4.1 months (IQR 2.2-5.4) post CAR T, with the majority of patients (48%) receiving transplant as first-line post CAR T. Reasons for allo-HCT were consolidation of complete response (CR) to CAR T in high-risk disease (n=4, 14 %), partial response (PR) to CAR T (n=7, 24%) and relapse /progression after CAR T (n=18, 62%). Disease response before allo-HCT was CR (n=11, 38%), PR (n=11, 38%) and progressive disease (n=7, 24%). Donors were matched siblings (n=13, 45%), matched unrelated (n=9, 31%) and mismatched unrelated /haploidentical donors (n=7, 24%). Myeloablative and reduced-intensity conditioning regimens were given in 13 (45%) and 16 (55%) patients, respectively. Methotrexate-based graft versus host disease (GVHD) prophylaxis was used in 20 (69%) patients. Antithymocyte globulin and post-transplantation cyclophosphamide were administered in 13 (45%) and 5 (14%), respectively. Results Median follow-up was 33 months (IQR 13-41). Neutrophil engraftment rate was 93% (two early deaths before engraftment due to infection and multi-organ failure). Two-year overall survival (OS) and progression-free survival were 44% (95% CI: 28-68) and 30% (95% CI: 17-55), respectively. Two-year cumulative relapse incidence and non-relapse mortality were 45% (95% CI: 25-63) and 25% (95% CI: 11-43), respectively (Figure). In a univariable Cox regression, factors significantly associated with a shorter OS were number of interim therapies between CAR T and allo-HCT (Hazard ratio [HR] 2.2 [95% CI: 1.3-3.9], p 0.006) and the length of time between CAR T and allo-HCT (HR 3.8 [95% CI: 1.2-12.1], p 0.02). Best response to CAR T and disease response before allo-HCT were not significant risk factors for a shorter OS. High rates of grade ≥ 3 hyperbilirubinemia (total bilirubin &gt;3 ULN) and hepatic sinusoidal obstruction syndrome (SOS) were observed in 10 (35%) and 5 (17%) patients, respectively. These liver insults were not contributed to acute GVHD. All patients with SOS were treated with defibrotide and two patients died from related complications. Interestingly, 4/5 patients with SOS were conditioned with fludarabine and thiotepa. One-year cumulative incidence of grade II-IV acute GVHD was 34% (n=10; 95% CI: 18-52). Notably, 6 patients had grade IV acute GVHD, 4 of them were refractory to corticosteroids and 3 patients died due to acute GVHD. Two-year cumulative incidence of chronic GVHD was 23% (n=5; 95% CI: 7-46). Chronic GVHD was considered extensive in 4 of them. Bloodstream bacterial infection was documented in 11 (38%) patients. Invasive fungal infection occurred in 6 (21%) patients and included brain aspergillosis, cutaneous aspergillosis, 2 lung aspergillosis, hepatosplenic candidiasis and an ocular mucor mycosis. Conclusion Allogeneic hematopoietic cell transplantation is feasible after failure of CAR T-cell therapy in aggressive lymphoma, although with a relatively high rate of SOS and severe acute GVHD in these heavily pretreated patients. Overall survival is encouraging with approximately 30% of patients remaining alive and disease-free at two years. Larger scale studies are required to better define the role of allo-HCT in this setting. Figure 1 Figure 1. Disclosures Shouval: Medexus: Consultancy. Jacoby: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avigdor: Takeda: Consultancy, Honoraria; Janssen: Research Funding; BMS: Research Funding; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Increased apoptosis of peripheral blood T cells following allogeneic hematopoietic cell transplantation

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3832-3839 ◽  
Author(s):  
Ming-Tseh Lin ◽  
Li-Hui Tseng ◽  
Haydar Frangoul ◽  
Ted Gooley ◽  
Ji Pei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Apoptosis ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Cd4 T Cell ◽  
Spontaneous Apoptosis ◽  
T Cell Apoptosis

Abstract Lymphopenia and immune deficiency are significant problems following allogeneic hematopoietic cell transplantation (HCT). It is largely assumed that delayed immune reconstruction is due to a profound decrease in thymus-dependent lymphopoiesis, especially in older patients, but apoptosis is also known to play a significant role in lymphocyte homeostasis. Peripheral T cells from patients who received HCT were studied for evidence of increased cell death. Spontaneous apoptosis was measured in CD3+ T cells following a 24-hour incubation using 7-amino-actinomycin D in conjunction with the dual staining of cell surface antigens. Apoptosis was significantly greater among CD3+ T cells taken from patients 19-23 days after transplantation (30.4% ± 12.5%,P &lt; .05), and 1 year after transplantation (9.7% ± 2.8%, P &lt; .05) compared with healthy controls (4.0% ± 1.5%). Increased apoptosis occurred preferentially in HLA (human leukocyte antigen)-DR positive cells and in both CD3+/CD4+ and CD3+/CD8+ T-cell subsets, while CD56+/CD3− natural killer cells were relatively resistant to apoptosis. The extent of CD4+T-cell apoptosis was greater in patients with grade II-IV acute graft-versus-host disease (GVHD) (33.9% ± 11.3%) compared with grade 0-I GVHD (14.6 ± 6.5%, P &lt; .05). T-cell apoptosis was also greater in patients who received transplantations from HLA-mismatched donors (39.5% ± 10.4%,P &lt; .05) or HLA-matched unrelated donors (32.1% ± 11.4%, P &lt; .05) compared with patients who received transplantations from HLA-identical siblings (19.6% ± 6.7%). The intensity of apoptosis among CD4+ T cells was significantly correlated with a lower CD4+ T-cell count. Together, these observations suggest that activation of T cells in vivo, presumably by alloantigens, predisposes the cells to spontaneous apoptosis, and this phenomenon is associated with lymphopenia. Activation-induced T-cell apoptosis may contribute to delayed immune reconstitution following HCT.

scholarly journals Features of repertoire diversity and gene expression in human cytotoxic T cells following allogeneic hematopoietic cell transplantation

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hideki Nakasone ◽  
Machiko Kusuda ◽  
Kiriko Terasako-Saito ◽  
Koji Kawamura ◽  
Yu Akahoshi ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cytotoxic T Cells ◽  
Cell Receptor ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Cytomegalovirus Reactivation

AbstractCytomegalovirus reactivation is still a critical concern following allogeneic hematopoietic cell transplantation, and cellular immune reconstitution of cytomegalovirus-specific cytotoxic T-cells is necessary for the long-term control of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation. Here we show the features of repertoire diversity and the gene expression profile of HLA-A24 cytomegalovirus-specific cytotoxic T-cells in actual recipients according to the cytomegalovirus reactivation pattern. A skewed preference for BV7 genes and sequential “G” amino acids motif is observed in complementarity-determining region-3 of T cell receptor-β. Increased binding scores are observed in T-cell clones with complementarity-determining region-3 of T cell receptor-β with a “(G)GG” motif. Single-cell RNA-sequence analyses demonstrate the homogenous distribution of the gene expression profile in individual cytomegalovirus-specific cytotoxic T-cells within each recipient. On the other hand, bulk RNA-sequence analyses reveal that gene expression profiles among patients are different according to the cytomegalovirus reactivation pattern, and are associated with cytokine production or cell division. These methods and results can help us to better understand immune reconstitution following hematopoietic cell transplantation, leading to future studies on the clinical application of adoptive T-cell therapies.

scholarly journals The Role of Immune Checkpoint Molecules for Relapse After Allogeneic Hematopoietic Cell Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Natalie Köhler ◽  
Dietrich Alexander Ruess ◽  
Rebecca Kesselring ◽  
Robert Zeiser
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Transplantation ◽  
Immune Checkpoint ◽  
Hematopoietic Cell Transplantation ◽  
Immune Checkpoint Blockade ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Immune Checkpoint Molecules

Immune checkpoint molecules represent physiological brakes of the immune system that are essential for the maintenance of immune homeostasis and prevention of autoimmunity. By inhibiting these negative regulators of the immune response, immune checkpoint blockade can increase anti-tumor immunity, but has been primarily successful in solid cancer therapy and Hodgkin lymphoma so far. Allogeneic hematopoietic cell transplantation (allo-HCT) is a well-established cellular immunotherapy option with the potential to cure hematological cancers, but relapse remains a major obstacle. Relapse after allo-HCT is mainly thought to be attributable to loss of the graft-versus-leukemia (GVL) effect and hence escape of tumor cells from the allogeneic immune response. One potential mechanism of immune escape from the GVL effect is the inhibition of allogeneic T cells via engagement of inhibitory receptors on their surface including PD-1, CTLA-4, TIM3, and others. This review provides an overview of current evidence for a role of immune checkpoint molecules for relapse and its treatment after allo-HCT, as well as discussion of the immune mediated side effect graft-vs.-host disease. We discuss the expression of different immune checkpoint molecules on leukemia cells and T cells in patients undergoing allo-HCT. Furthermore, we review mechanistic insights gained from preclinical studies and summarize clinical trials assessing immune checkpoint blockade for relapse after allo-HCT.

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