Comparison of and Immune Reconstitution and Graft Versus Host Disease in 30mg/Kg Anti-T-Lymphocyte Globuline with 60mg/Kg ATLG As Graft Versus Host Disease Prophylaxis in Matched Unrelated Donor Myeloablative Peripheral Blood Stem Cell Transplantation

Abstract Introduction: Data on the influence of different ATLG doses on immune reconstitution (IR) and GvHD in MUD allo-SCT is limited. In this study, we compared the impact of ATLG doses (30mg/kg vs 60 mg/kg) on IR and transplant outcomes. Methods: In this retrospective study we included 289 patients who received MUD allografts (HLA 10/10) between 2005-2019 in the University Cance Center University of Hamburg. All patients received PBSC-allo-SCT with MAC for various hematological malignancies. Seventy-three patients received 30mg/kg ATLG, and 216 patients received 60mg/kg (on days -3.-2 and -1) prior to allo-SCT. Periphereal blood samples were collected on days +30, +100 and +180 and analyzed by flow cytometry for following lymphocyte populations: T-cells (total and activated), T-helper cells (total, naïve and memory), cytotoxic T-cells (total, naïve and memory), B-Lymphocytes (total, naïve and memory), NK-cells, NKT-cells, γδT-cells and regulatory T-cells. Results: Neutrophil and platelet engraftments were significantly delayed after the 60mg/kg compared to 30mg/kg group with medians of 11 days (range, 8-23) vs 12 days (8-27) (p=0.009) for neutrophil and 14 days (range, 9-53) vs 16 days (range, 8-237) for platelets, respectively (p=0.002). We observed a higher incidence of EBV reactivation within the first 100 days in the 60mg/kg group (41% vs 21% in the 30mg/kg group, p=0.049). Higher cumulative incidence of Infections Day +100 was observed in the 60 mg/Kg group with an incidence of 75% vs that of 67% in the 30mg/Kg group respectively (p=0.002). At day +30 we observed a faster reconstitution of naïve-B cells (p<0.0001) and γδ T cells (p=0.045) in the 30mg/kg group. No significant differences in IR were observed at day +100. At day +180 the use of 30mg/Kg was associated with a faster naïve helper T-cell (p=0.046), NK-cells (p=0.035), and naïve B-cell reconstitution (p=0.009). The incidence of aGVHD grade II-IV was comparable between the groups: 63% and 59% in the 30mg/Kg and 60mg/Kg groups, respectively. We observed a higher incidence of grade IV aGvHD in the 30mg/kg group (8%) comparing with the rate of 0.5% in the 60mg/kg group (p=0.0002), this was confirmed in multivariate analysis: RR 0.65 (95%CI 0.005-0.363) p= 0.004. After a median follow up of 21 months (range, 1-161) there were no significant differences in OS, PFS, NRM, RI and cGVHD between the groups. Conclusion: The choice of ATLG dose has significant impact on IR after MUD-allo-SCT. Higher doses are associated with reduced severe aGVHD, however at the cost of delaying engraftment and increasing infections. Disclosures Ayuk: Celgene/BMS: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Miltenyi Biomedicine: Honoraria; Novartis: Honoraria; Takeda: Honoraria.

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

Blood ◽

10.1182/blood-2005-04-1614 ◽

2005 ◽

Vol 106 (9) ◽

pp. 3308-3313 ◽

Cited By ~ 77

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.

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A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease

Blood ◽

10.1182/blood.v95.12.3693 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3693-3701 ◽

Cited By ~ 26

Author(s):

Ypke V. J. M. van Oosterhout ◽

Liesbeth van Emst ◽

Anton V. M. B. Schattenberg ◽

Wil J. M. Tax ◽

Dirk J. Ruiter ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Graft Versus Host Disease ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Host Disease ◽

Graft Versus Host ◽

Ricin A

Abstract This study evaluated the anti-graft versus host disease (GVHD) potential of a combination of immunotoxins (IT), consisting of a murine CD3 (SPV-T3a) and CD7 (WT1) monoclonal antibody both conjugated to deglycosylated ricin A. In vitro efficacy data demonstrated that these IT act synergistically, resulting in an approximately 99% elimination of activated T cells at 10−8 mol/L (about 1.8 μg/mL). Because most natural killer (NK) cells are CD7+, NK activity was inhibited as well. Apart from the killing mediated by ricin A, binding of SPV-T3a by itself impaired in vitro cytotoxic T-cell cytotoxicity. Flow cytometric analysis revealed that this was due to both modulation of the CD3/T-cell receptor complex and activation-induced cell death. These results warranted evaluation of the IT combination in patients with refractory acute GVHD in an ongoing pilot study. So far, 4 patients have been treated with 3 to 4 infusions of 2 or 4 mg/m2 IT combination, administered intravenously at 48-hour intervals. The T1/2 was 6.7 hours, and peak serum levels ranged from 258 to 3210 ng/mL. Drug-associated side effects were restricted to limited edema, fever, and a modest rise of creatine kinase levels. One patient developed low-titer antibodies against ricin A. Infusions were associated with an immediate drop of circulating T cells, followed by a more gradual but continuing elimination of T/NK cells. One patient mounted an extensive CD8 T-cell response directly after treatment, not accompanied with aggravating GVHD. Two patients showed nearly complete remission of GVHD, despite unresponsiveness to the extensive pretreatment. These findings justify further investigation of the IT combination for treatment of diseases mediated by T cells.

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Protection of the Intestinal Epithelium from Conditioning with R-spondin1 Ameliorates Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v112.11.66.66 ◽

2008 ◽

Vol 112 (11) ◽

pp. 66-66 ◽

Cited By ~ 2

Author(s):

Shuichiro Takashima ◽

Kazutoshi Aoyama ◽

Motoko Koyama ◽

Daigo Hashimoto ◽

Takeshi Oshima ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Large Bowel ◽

Immune Reconstitution ◽

Allogeneic Bone ◽

Gi Tract ◽

Host Disease ◽

Graft Versus Host ◽

Tract Damage

Abstract Damage to the gastrointestinal (GI) tract by pretransplant conditioning regimen plays a critical role in amplifying graft-versus-host disease (GVHD). Thus protection of the GI tract from conditioning may represent a novel approach to prevent GVHD. R-Spondin1 (R-Spo1) is a novel class of soluble activator for Wnt/□-catenin signaling, and has potent and specific proliferative effects on the intestinal crypt cells; injection of R-Spo1 protects mice from chemotherapy-induced intestinal mucositis. We therefore hypothesized that administration of R-Spo1 could modulate GVHD by reducing the GI tract damage and improve outcome of allogeneic bone marrow transplantation (BMT). Lethally irradiated B6D2F1 (H-2b/d) mice were injected with 5 × 106 BM and 2 × 106 T cells from MHC-mismatched B6 (H-2b) donors on day 0. Mice were intravenously injected with 200 μg of R-Spo1 or diluent from days −3 to −1 and +1 to +3 after BMT. In vivo labeling assay of mitotic cells with BrdU demonstrated that the proliferative index, as determined by the percentages of BrdU-positive cells among crypt epithelial cells, was significantly greater in the small intestine of R-Spo1 treated mice than controls 4 days after BMT (57% ± 3% vs 48% ± 1%, P<0.05). Analysis of the mesenteric lymph nodes and spleens on day +7 demonstrated significantly reduced expansion of donor T cells in R-Spo1 treated recipients in association with reduced serum levels of IFN-□ and TNF-□ on day +7 when compared to controls (Table). GVHD was severe in allogeneic controls, with 12.5% survival by day +40, whereas 62.5% of R-Spo1-treated animals survived this period (Table). Histopathologic examination of the small and large bowel and liver showed significantly reduced GVHD pathology in R-Spo1 treated animals than in controls (Table). A flowcytometric analysis of the spleen and thymus after BMT showed that administration of R-Spo1 did not impair donor cell engraftment and T and B cell immune reconstitution. We next evaluated the impact of R-Spo1 on graft-versus-leukemia (GVL) effects. BMT was performed similarly as above with the addition of 5 × 104 host-type P815 leukemia cells (H-2d). All recipients of T cell-depleted BM died from leukemia by day +20 after BMT, while no leukemia death was observed in R-Spo1 treated allogeneic animals. Overall, R-Spo1 treatment improved outcome of allogeneic BMT by reducing GVHD, while maintaining immune reconstitution and GVL effects. Thus, administration of R-Spo1 reduces the GI tract damage and suppresses donor T cell activation and systemic GVHD, supporting a hypothesis that the GI tract plays a major role in the amplification of systemic GVHD. Brief treatment with R-Spo1 may serve as an effective adjunct to clinical regimens of GVHD prophylaxis. Pathology Scores Group Survivals on day+40 (%) Small bowel Large bowel Liver INF □ (ng/ml) TNF □ (pg/ml) TCD: T cell-depleted BMT, +T: T cell-repleted BMT, ND: not detected Data are expressed as mean ± SD. *P<0.01 vs control, **P<0.05 vs control TCD diluent 100 2.4± 0.9 3.5± 1.0 0.3± 0.3 ND ND +T diluent 12.5 8.3± 2.7 7.3± 1.9 2.0± 0.8 6.0 ± 2.4 103.7 ± 9.9 +T R-Spo1 62.5* 3.4±1.9** 3.9± 0.3** 0.8± 0.7** 2.3 ± 1.5** 55.4 ± 6.6**

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Critical role of host γδ T cells in experimental acute graft-versus-host disease

Blood ◽

10.1182/blood-2004-10-4087 ◽

2005 ◽

Vol 106 (2) ◽

pp. 749-755 ◽

Cited By ~ 37

Author(s):

Yoshinobu Maeda ◽

Pavan Reddy ◽

Kathleen P. Lowler ◽

Chen Liu ◽

Dennis Keith Bishop ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Critical Role ◽

Γδ T Cells ◽

Allogeneic Bone ◽

Host Disease ◽

Graft Versus Host ◽

Tnf Α

Abstract γδ T cells localize to target tissues of graft-versus-host disease (GVHD) and therefore we investigated the role of host γδ T cells in the pathogenesis of acute GVHD in several well-characterized allogeneic bone marrow transplantation (BMT) models. Depletion of host γδ T cells in wild-type (wt) B6 recipients by administration of anti-T-cell receptor (TCR) γδ monoclonal antibody reduced GVHD, and γδ T-cell-deficient (γδ-/-) BM transplant recipients experienced markedly improved survival compared with normal controls (63% vs 10%, P < .001). γδ T cells were responsible for this difference because reconstitution of γδ-/- recipients with γδ T cells restored GVHD mortality. γδ-/- recipients showed decreased serum levels of tumor necrosis factor α (TNF-α), less GVHD histopathologic damage, and reduced donor T-cell expansion. Mechanistic analysis of this phenomenon demonstrated that dendritic cells (DCs) from γδ-/- recipients exhibited less allostimulatory capacity compared to wt DCs after irradiation. Normal DCs derived from BM caused greater allogeneic T-cell proliferation when cocultured with γδ T cells than DCs cocultured with medium alone. This enhancement did not depend on interferon γ (IFN-γ), TNF-α, or CD40 ligand but did depend on cell-to-cell contact. These data demonstrated that the host γδ T cells exacerbate GVHD by enhancing the allostimulatory capacity of host antigen-presenting cells. (Blood. 2005;106:749-755)

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Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT

Blood ◽

10.1182/blood-2007-01-065383 ◽

2007 ◽

Vol 109 (11) ◽

pp. 5058-5061 ◽

Cited By ~ 203

Author(s):

Jeffery S. Miller ◽

Sarah Cooley ◽

Peter Parham ◽

Sherif S. Farag ◽

Michael R. Verneris ◽

...

Keyword(s):

Nk Cells ◽

Graft Versus Host Disease ◽

Myeloid Leukemia ◽

Hematopoietic Cell Transplantation ◽

Nk Cell ◽

Unrelated Donor ◽

Host Disease ◽

Graft Versus Host ◽

Grade 3 ◽

Genetically Determined

Abstract Natural killer (NK) cells can alter the outcome of hematopoietic cell transplantation (HCT) if donor alloreactivity targets the recipient. Since most NK cells express inhibitory killer-immunoglobulin receptors (KIRs), we hypothesized that the susceptibility of recipient cells to donor NK cell–mediated lysis is genetically predetermined by the absence of known KIR ligands. We analyzed data from 2062 patients undergoing unrelated donor HCT for acute myeloid leukemia (AML; n = 556), chronic myeloid leukemia (CML; n = 1224), and myelodysplastic syndrome (MDS; n = 282). Missing 1 or more KIR ligands versus the presence of all ligands protected against relapse in patients with early myeloid leukemia (relative risk [RR] = 0.54; n = 536, 95% confidence interval [CI] 0.30-0.95, P = .03). In the subset of CML patients that received a transplant beyond 1 year from diagnosis (n = 479), missing a KIR ligand independently predicted a greater risk of developing grade 3-4 acute graft-versus-host disease (GVHD; RR = 1.58, 95% CI 1.13-2.22; P = .008). These data support a genetically determined role for NK cells following unrelated HCT in myeloid leukemia.

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Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease

Journal of Clinical Oncology ◽

10.1200/jco.21.01755 ◽

2022 ◽

Author(s):

Marie Bleakley ◽

Alison Sehgal ◽

Stuart Seropian ◽

Melinda A. Biernacki ◽

Elizabeth F. Krakow ◽

...

Keyword(s):

T Cells ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Cumulative Incidence ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Unrelated Donor ◽

Host Disease ◽

Graft Versus Host ◽

Grade Iii

PURPOSE Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

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Anti-Chronic Graft Versus Host Disease Activity Though a Regulatory T Cell Dependent Mechanism after Photodynamic Therapy.

Blood ◽

10.1182/blood.v110.11.3280.3280 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3280-3280

Author(s):

Jean-Philippe Bastien ◽

Gorazd Krosl ◽

Pascale Dube ◽

Cynthia Therien ◽

Christian Scotto ◽

...

Keyword(s):

T Cells ◽

Photodynamic Therapy ◽

T Lymphocytes ◽

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Inhibitory Effect ◽

Activated T Cells ◽

Host Disease ◽

Graft Versus Host ◽

The Impact

Abstract Graft-versus-host disease (GVHD) is the principal cause of morbidity and mortality after hematopoietic stem cell transplantation. Even the most potent immunosuppressive agents often fail to control GVHD. Because of its unique cell-mediated approach, photopheresis represents an appealing alternative for the treatment of GVHD, particularly in its chronic form. Photodynamic therapy (PDT) using TH9402 (4,5-dibromorhodamine methyl ester), a photosensitizer, which upon activation with visible light, exhibits specific toxicity against activated T lymphocytes, while preserving resting T cells, has emerged as a potentially interesting alternative treatment modality for GVHD patients. However, the immunologic mechanisms involved in GVHD modulation by PDT still remain obscure. Since CD4+CD25+FoxP3+ regulatory T cells (Tregs) have an inhibitory effect on GVHD, we sought to determine the role of Tregs in the context of photopheresis using TH9402 for GVHD modulation. We first evaluated, using flow cytometry, the impact of PDT on activated T cells and Tregs obtained from steroid-refractory chronic GVHD patients. High (10 uM) and low (1,32 uM) TH9402 concentrations were compared to measure their ability preserve Tregs. Interestingly, low intensity TH9402 treatment demontrated particularly interesting features, resulting in the elimination of more than 90% of activated CD4+CD25+FoxP3- and CD4+CD44high T cells, while preserving 95% of CD4+CD25+ FoxP3+ cells (p<0.001; n=5 pts). The proportion of live CD4+CD25+ FoxP3+ cells increased from 51.8±5.2% to 89.0±5.9% (mean±SD; pre and post PDT, respectively; p<0.01) thus enriching the graft in Tregs. Next, we evaluated the ability of PDT treated mononuclear cells to inhibit the proliferation of untreated MNCs from cGVHD pts. The addition of PDT cells reduced the proliferation of cGVHD T lymphocytes by 41–76% (p<0.001, n=6 pts). This inhibitory effect disappeared following inhibition of Pgp-171 by verapamil, which promoted TH9402 intracellular retention and effector cell elimination upon light exposure, indicating that Tregs must not only be present but viable to exert their suppressive activity. In addition, higher levels of IL-10, but not TGF-β, were secreted when cGVHD cells were exposed to PDT-treated cells (34.7±5.1ng/mL) than when exposed to untreated cells (20.3±3.2ng/mL, p<0.05). Furthermore, the inhibitory effect decreased 5-fold when cGVHD cells were co-cultured for 6 days with CD4+CD25+ depleted PDT cells (p<0.001). Addition of anti-IL-10 monoclonal antibody (mAb) to the co-culture (PDT-treated cells with cGVHD cells) resulted in a 3-fold decrease in the inhibition of cGVHD cell proliferation mediated by PDT-treated cells (p<0.01) and a 1.5-fold decrease when anti-TGF-β mAb was added to the co-culture (p<0.05). In conclusion, our results demonstrate that TH9402 PDT not only eliminates activated T cells, but preserves Tregs, with the functional ability to inhibit residual alloreactive cGVHD cells. This inhibitory effect requires live effector Tregs, secretion of IL-10 and TGF-β expression. With such dual effector mechanisms, photopheresis using TH9402 should translate into improved treatment efficacy and enhanced quality of life for patients with chronic GVHD.

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Rapid Recovery of CD4 Counts Following Low Dose Alemtuzumab Conditioning During HLA Matched Related Bone Marrow Transplant for Children with Haemoglobinopathies

Blood ◽

10.1182/blood.v116.21.2335.2335 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2335-2335

Author(s):

Lucy Cook ◽

Farah O'Boyle ◽

Leena Karnik ◽

Helen New ◽

Irene Roberts ◽

...

Keyword(s):

Cell Count ◽

Graft Versus Host Disease ◽

Immune Reconstitution ◽

Low Dose ◽

Cell Recovery ◽

Host Disease ◽

Graft Versus Host ◽

Cd4 Cell ◽

The Impact ◽

Cmv Reactivation

Abstract Abstract 2335 CMV viraemia and disease remains a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). We investigated the impact of low dose alemtuzumab conditioning in paediatric matched sibling allogeneic BMT for haemoglobinopathy on immune reconstitution (early and late CD3/4+, CD3/8+, CD3-/CD56+ cell recovery) and subsequent viral infections in 18 consecutive transplants (14 β thalassaemia major and 4 sickle cell anaemia). A secondary aim was to investigate the impact of immune reconstitution on graft versus host disease but due to the extremely low incidence of acute and chronic graft versus host disease with this protocol (acute grade II to IV 11.6% and chronic 4.6%) we were unable to assess this. Transplant protocol: following hypertransfusion to suppress endogenous haemopoiesis, patients were conditioned with oral busulfan 14 mg/kg (days -9 to -6), cyclophosphamide 200 mg/kg (days -5 to -2) and alemtuzumab 0.3 mg/kg (days -8 to -6). Graft versus host disease prophylaxis was provided with ciclosporin for six months and methotrexate 10 mg/m2 on days +4 and +7. All transplants used BM as source of stem cells. CMV PCR surveillance was undertaken twice weekly and CMV reactivation was treated with intravenous foscarnet or ganciclovir, followed by secondary prophylaxis with valganciclovir. Routine peripheral blood immunophenotyping of lymphocyte subsets was performed at 60-, 90-, 120-, 150- and 180- days post-BMT. Results: the median age of transplant recipients was 7 years (range 2 – 17 years) and median follow up 254 days (range 203–378). The median CD3/CD4+ cell count rose above 200 cells/μl by day 180 and above 300 cells/μl by day 254 following the withdrawal of immune suppression at six months (fig 1A), the median CD8+ cell count increased earlier, to >200 cells/μl by day 60 and 300 cells/μl by day 180 (fig 1B) and the median CD56+ cell count reached 200 cells/μl by day 60 and plateaued thereafter (fig 1C). Overall, CMV reactivation occurred in 13 patients (72.2%) after a median interval of 35 days following BM infusion (range day-1 to day +72): 10/13 patients (76.9%) in whom both recipient and donor were CMV positive (CMV +/+); 1/3 patients in whom recipient was CMV negative and donor CMV positive (CMV -/+); and in 1/1 who was CMV positive with a CMV negative donor (CMV +/−). Significantly there was no clinical CMV disease in any patient and with the use of oral valganciclovir there were no subsequent CMV reactivations. CMV reactivation occurred in patients with lower CD4+ cell counts at day 60 (67 cells/μl) compared with the CMV-unaffected group (a median CD4+ count 298 cells/μl; p= 0.0262). Four patients experienced other viral infections: HHV6 infection requiring foscarnet on day +85 (n=1), urinary BK virus not requiring treatment (n=2) and parainfluenza pneumonitis requiring ribavarin on day +12 (n=1). Conclusion: Low dose alemtuzumab conditioning is associated with rapid CD4+ cell recovery (CD4+ >200 cells/μl by day +180) in children undergoing allogeneic matched related donor BMT for haemoglobinopathy. Although there is a high frequency of CMV reactivation (72.2%) in patients with low CD4+ counts at day 60 (median CD4+ count 67 cells/μl), no clinical CMV disease was seen and subsequent reactivations of CMV were prevented by the use of valganciclovir secondary prophylaxis whilst awaiting full immune reconstitution. Disclosures: No relevant conflicts of interest to declare.

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Massive Activation-Induced Cell Death of Alloreactive T Cells With Apoptosis of Bystander Postthymic T Cells Prevents Immune Reconstitution in Mice With Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v94.2.390.414k27_390_400 ◽

1999 ◽

Vol 94 (2) ◽

pp. 390-400 ◽

Cited By ~ 1

Author(s):

Sylvie Brochu ◽

Benjamin Rioux-Massé ◽

Jean Roy ◽

Denis-Claude Roy ◽

Claude Perreault

Keyword(s):

T Cells ◽

Cell Death ◽

Graft Versus Host Disease ◽

Immune Reconstitution ◽

Chronic Phase ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Activation Induced Cell Death ◽

Alloreactive T Cells

After hematopoietic stem cell transplantation, the persistence and expansion of grafted mature postthymic T cells allow both transfer of donor immunologic memory and generation of a diverse T repertoire. This thymic-independent process, which is particularly important in humans, because most transplant recipients present severe thymus atrophy, is impaired by graft-versus-host disease (GVHD). The goal of this study was to decipher how GVHD influences the fate of grafted postthymic T cells. Two major findings emerged. First, we found that, after a brisk proliferation phase, alloreactive antihost T cells underwent a massive activation-induced cell death (AICD). For both CD4+ and CD8+ T cells, the Fas pathway was found to play a major role in this AICD: alloreactive T cells upregulated Fas and FasL, and AICD of antihost T cells was much decreased in the case of lpr (Fas-deficient) donors. Second, whereas non–host-reactive donor T cells neither upregulated Fas nor suffered apoptosis when transplanted alone, they showed increased membrane Fas expression and apoptosis when coinjected with host-reactive T cells. We conclude that GVHD-associated AICD of antihost T cells coupled with bystander lysis of grafted non–host-reactive T cells abrogate immune reconstitution by donor-derived postthymic T lymphocytes. Furthermore, we speculate that massive lymphoid apoptosis observed in the acute phase of GVHD might be responsible for the occurrence of autoimmunity in the chronic phase of GVHD.

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