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

Blood ◽  
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.

Tregs In Graft-Versus-Host Disease: A Task Force In Trouble?.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3748-3748
Author(s):  
Sya N. Ukena ◽  
Jens Grosse ◽  
Stefanie Buchholz ◽  
Michael Stadler ◽  
Arnold Ganser ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Peripheral Tolerance ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact

Abstract Abstract 3748 Graft-versus-host disease (GvHD) remains the major clinical complication in hematopoietic stem cell transplantation (SCT) resulting in severe morbidity and significant mortality. This alloreactive immune response is mainly induced by donor T cells transplanted with the graft. Regulatory T cells (Tregs) play an essential role in the induction and maintenance of peripheral tolerance. In addition, data from murine models have shown that Tregs can prevent GvHD while preserving the graft-versus-leukemia effect. In order to functionally and dynamically characterize human Tregs after allogeneic SCT, we analyzed CD4+CD25highCD127dim T cells isolated from the peripheral blood of more than 80 patients with hematological malignancies every 30 days over half a year following SCT. Patients were divided into the following clinical groups: (A) no signs of acute or chronic GvHD, (B) acute GvHD, (C) chronic GvHD and (D) acute GvHD passed into chronic GvHD. Human peripheral blood lymphocytes were separated by Ficoll gradient and CD4+CD14−CD25highCD127dim T cells were isolated by MoFlow cell sorting. Isolated RNA was pooled and microarray analysis was performed by using Affymetrix HG_U133_Plus2.0 Arrays. Results were verified by using quantitative realtime RT-PCR. Additionally, Tregs were phenotypically analyzed by FACS. We monitored a continous but slower recovery of Tregs in GvHD within the first 6 months following PBSCT. Manifestation of acute and chronic GvHD correlated with significantly reduced frequencies of peripheral Tregs in the first month after PBSCT compared to patients without GvHD. Microarray data revealed a high stability of the Treg transcriptome in the first half year representing the most sensitive time window for tolerance induction. Moreover, comparison of the Treg gene expression profiles from patients with and without GvHD point to a reduced suppressive function of Tregs with diminished migration capacity to the target organs likely contributing to the development of GvHD. Our findings corroborate the impact of human Tregs in the pathophysiology of GvHD and identify novel targets for the manipulation of Tregs to optimize strategies for prophylaxis and treatment of life-threatening GvHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Aberrant regulation of superantigen responses during T-cell reconstitution and graft-versus-host disease in immunodeficient mice

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2216-2224
Author(s):  
David Spaner ◽  
Xiaofang Sheng-Tanner ◽  
Andre C. Schuh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Adoptive Transfer ◽  
Scid Mice ◽  
Control Mechanisms ◽  
Activated T Cells ◽  
Host Disease ◽  
Immunodeficient Mice ◽  
Graft Versus Host

Acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation is associated with impaired deletion and anergy of host-reactive T cells. To elucidate the immunoregulatory events that may contribute to such dysregulated T-cell responses in GVHD, we studied superantigen (SAg) responses after adoptive T-cell transfer into severe combined immunodeficient (SCID) mice. SAg responses are normally regulated by mechanisms involving deletion and anergy, with SAg-reactive T cells typically being deleted rapidly in vivo. In a SCID mouse model of GVHD, however, allogeneic host SAg-reactive T cells were not deleted rapidly, but rather persisted in increased numbers for several months. Moreover, depending on the timing of SAg stimulation and the numbers of T cells transferred, dysregulation (impaired deletion and anergy) of SAg responses could be demonstrated following the adoptive transfer of syngeneic T cells into SCID mice as well. Transgenic T-cell receptor-bearing KJ1-26.1+ T cells were then used to determine the fate of weakly reactive T cells after adoptive transfer and SAg stimulation. When transferred alone, KJ1-26.1+ T cells demonstrated impaired deletion and anergy. In the presence of more strongly staphylococcal enterotoxin B (SEB)–reactive T cells, however, KJ1-26.1+ T cells were regulated normally, in a manner that could be prevented by inhibiting the effects of more strongly SEB-reactive cells or by increasing the level of activation of the KJ1-26.1+ T cells themselves. We suggest that the control mechanisms that normally regulate strongly activated T cells in immunocompetent animals are lost following adoptive transfer into immunodeficient hosts, and that this impairment contributes to the development of GVHD.

scholarly journals Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1756-1764 ◽  
Author(s):  
Yukimi Sakoda ◽  
Daigo Hashimoto ◽  
Shoji Asakura ◽  
Kengo Takeuchi ◽  
Mine Harada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

Abstract Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell–depleted bone marrow cells from major histocompatibility complex [MHC] class II–deficient (H2-Ab1−/−) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.

scholarly journals Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3804-3813 ◽  
Author(s):  
Xiao Chen ◽  
Sanja Vodanovic-Jankovic ◽  
Bryon Johnson ◽  
Melissa Keller ◽  
Richard Komorowski ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Th17 Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) remains the major complication after allogeneic bone marrow transplantation (BMT). The process whereby acute GVHD mediated by alloreactive donor T cells transitions into chronic GVHD, which is characterized by prominent features of auto-immunity, has long been unresolved. In this study, we demonstrate that GVHD-associated autoimmunity and, by extension, chronic GVHD is attributable to the progressive loss of CD4+CD25+Foxp3+ regulatory T cells during the course of acute GVHD. This leads to the expansion of donor-derived CD4+ T cells with TH1 and TH17 cytokine phenotypes that release proinflammatory cytokines and cause autoimmune-mediated pathological damage. These T cells are present early after transplantation, indicating that the pathophysiological events that lead to chronic GVHD are set in motion during the acute phase of GVHD. We conclude that the absence of CD4+CD25+ regulatory T cells coupled with unregulated TH1 and TH17 cells leads to the development of autoimmunity and that donor-derived TH1 and TH17 cells serve as the nexus between acute and chronic GVHD.

scholarly journals Interleukin-12 Preserves the Graft-Versus-Leukemia Effect of Allogeneic CD8 T Cells While Inhibiting CD4-Dependent Graft-Versus-Host Disease in Mice

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4651-4660 ◽  
Author(s):  
Yong-Guang Yang ◽  
Justin J. Sergio ◽  
Denise A. Pearson ◽  
Gregory L. Szot ◽  
Akira Shimizu ◽  
...  
Keyword(s):  
T Cells ◽  
Protective Effect ◽  
Graft Versus Host Disease ◽  
Inhibitory Effect ◽  
Interleukin 12 ◽  
Spleen Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Ifn Γ

We have recently demonstrated that a single injection of 4,900 IU of interleukin-12 (IL-12) on the day of bone marrow transplantation (BMT) markedly inhibits acute graft-versus-host disease (GVHD) in a fully major histocompatibility complex plus minor antigen-mismatched BMT model (A/J → B10, H-2a → H-2b), in which donor CD4+ T cells are required for the induction of acute GVHD. We show here that donor CD8-dependent graft-versus-leukemia (GVL) effects against EL4 (H-2b) leukemia/lymphoma can be preserved while GVHD is inhibited by IL-12 in this model. In mice in which IL-12 mediated a significant protective effect against GVHD, marked GVL effects of allogeneic T cells against EL4 were observed. GVL effects against EL4 depended on CD8-mediated alloreactivity, protection was not observed in recipients of either syngeneic (B10) or CD8-depleted allogeneic spleen cells. Furthermore, we analyzed IL-12–treated recipients of EL4 and A/J spleen cells which survived for more than 100 days. No EL4 cells were detected in these mice by flow cytometry, tissue culture, adoptive transfer, necropsies, or histologic examination. Both GVL effects and the inhibitory effect of IL-12 on GVHD were diminished by neutralizing anti–interferon-γ (IFN-γ) monoclonal antibody. This study demonstrates that IL-12–induced IFN-γ production plays a role in the protective effect of IL-12 against GVHD. Furthermore, IFN-γ is involved in the GVL effect against EL4 leukemia, demonstrating that protection from CD4-mediated GVHD and CD8-dependent anti-leukemic activity can be provided by a single cytokine, IFN-γ. These observations may provide the basis for a new approach to inhibiting GVHD while preserving GVL effects of alloreactivity.

Role of CD28 in Acute Graft-Versus-Host Disease

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2963-2970 ◽  
Author(s):  
Xue-Zhong Yu ◽  
Paul J. Martin ◽  
Claudio Anasetti
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class I ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Class I ◽  
Host Disease ◽  
Cd8 Cells ◽  
Graft Versus Host

Because CD28-mediated T-cell costimulation has a pivotal role in the initiation and maintenance of T-cell responses, we tested the hypothesis that CD28 is critical for the development of graft-versus-host disease (GVHD). We compared the in vivo effects of CD28−/− T cells transplanted from B6 donor with the CD28 gene deleted by homologous recombination with those of CD28+/+ T cells transplanted from wild-type C57BL/6 (B6) donor. Fifty million CD28−/− or CD28+/+ splenocytes from B6 mice were transplanted into unirradiated (B6 × DBA/2)F1 (BDF1) recipients. Unlike CD28+/+, CD28−/− T cells from B6 mice had lower levels of proliferation and interleukin-2 production, had a limited ability to generate cytotoxic T lymphocytes against the recipient, and did not induce immune deficiency, despite survival in the recipient for at least 28 days. The ability to prevent rejection was reduced by the absence of CD28, because as many as 1.0 × 107 CD28−/− CD8+ cells were needed to prevent rejection of major histocompatibility complex (MHC) class-I incompatible marrow in sublethally irradiated (550 cGy) bm1 recipients, whereas 8.0 × 105 CD28+/+CD8+ T cells were sufficient to produce a similar effect, indicating that CD28 on donor CD8+ cells helps to eliminate host immunity. Two million CD4+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-II incompatible (B6 × bm12)F1 recipients. With CD28−/−cells, 44% of the recipients died at a median of 20 days compared with 94% at a median of 15 days with CD28+/+ cells (P < .001). Two million CD8+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-I incompatible (B6 × bm1) F1 recipients. With CD28−/−cells, 25% of the recipients died at a median of 41 days compared with 100% at a median of 15 days with CD28+/+ cells (P < .001). (B6 × bm12)F1 and (B6 × bm1)F1 mice surviving after transplantation of CD28−/− cells recovered thymocytes, T cells, and B cells in numbers and function comparable with that of irradiation-control F1 mice. We conclude that CD28 contributes to the pathogenesis and the severity of GVHD. Our results suggest that the severity of GVHD could be decreased by the administration of agents that block CD28 function in T lymphocytes. © 1998 by The American Society of Hematology.

Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 941-947 ◽  
Author(s):  
Gullu Gorgun ◽  
Kenneth B. Miller ◽  
Francine M. Foss
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Clinical Response ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Extracorporeal Photochemotherapy ◽  
Graft Versus Host ◽  
Antigen Presenting

Abstract Extracorporeal photochemotherapy (ECP) has been shown to be an effective therapy for patients with acute and chronic graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation, but its biologic mechanism is not understood. We reported that clinical response to ECP was associated not only with normalization of skewed CD4/CD8 ratios but also with an increase in CD3−/CD56+ natural killer cells and a decrease in the number of CD80+ and CD123+ circulating dendritic cells (DCs). To further elucidate the effects of ECP on activated lymphocyte subpopulations and the interaction between effector lymphocytes and antigen-presenting DCs, we isolated and characterized DC populations from patients with chronic GVHD undergoing ECP therapy. Antigen-presenting activity of DCs was measured as proliferation of antigen-stimulated autologous and allogeneic T cells by mixed-lymphocyte reaction (MLR). In MLR assays the proliferation of T cells was decreased in all 10 patients by a mean of 84% (range, 75%-95%; P ≤ .002) after a 2-day cycle of ECP and longitudinally over the 12-month course of therapy. Immunophenotypic analysis of DC populations revealed a preponderance of DC1 monocytic dendritic cells in all patients before the initiation of ECP. Nine of 10 patients demonstrated a shift from DC1 to DC2 and as a concordant shift from a predominantly Th1 (interleukin-2 [IL-2], interferon-γ) to Th2 (IL-4, IL-10) cytokine profile after ECP, and 8 of 10 had a clinical response to ECP. Our results suggest that ECP alters alloreactivity by affecting allo-targeted effector T cells and antigen-presenting DCs.

scholarly journals Application of Photodynamic Therapy with 5-Aminolevulinic Acid to Extracorporeal Photopheresis in the Treatment of Patients with Chronic Graft-versus-Host Disease: A First-in-Human Study

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1558
Author(s):  
Eidi Christensen ◽  
Olav A. Foss ◽  
Petter Quist-Paulsen ◽  
Ingrid Staur ◽  
Frode Pettersen ◽  
...  
Keyword(s):  
T Cells ◽  
Photodynamic Therapy ◽  
Adverse Events ◽  
Graft Versus Host Disease ◽  
Aminolevulinic Acid ◽  
White Blood Cells ◽  
Human Study ◽  
Extracorporeal Photopheresis ◽  
Host Disease ◽  
Graft Versus Host

Extracorporeal photopheresis (ECP), an immunomodulatory therapy for the treatment of chronic graft-versus-host disease (cGvHD), exposes isolated white blood cells to photoactivatable 8-methoxypsoralen (8-MOP) and UVA light to induce the apoptosis of T-cells and, hence, to modulate immune responses. However, 8-MOP-ECP kills diseased and healthy cells with no selectivity and has limited efficacy in many cases. The use of 5-aminolevulinic acid (ALA) and light (ALA-based photodynamic therapy) may be an alternative, as ex vivo investigations show that ALA-ECP kills T-cells from cGvHD patients more selectively and efficiently than those treated with 8-MOP-ECP. The purpose of this phase I-(II) study was to evaluate the safety and tolerability of ALA-ECP in cGvHD patients. The study included 82 treatments in five patients. One patient was discharged due to the progression of the haematological disease. No significant persistent changes in vital signs or laboratory values were detected. In total, 62 adverse events were reported. Two events were severe, 17 were moderate, and 43 were mild symptoms. None of the adverse events evaluated by the internal safety review committee were considered to be likely related to the study medication. The results indicate that ALA-ECP is safe and is mainly tolerated well by cGvHD patients.

scholarly journals 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

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3897-3897
Author(s):  
Radwan Massoud ◽  
Evgeny Klyuchnikov ◽  
Nico Gagelmann ◽  
Tatjana Zabelina ◽  
Wolschke Christine ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Graft Versus Host Disease ◽  
Immune Reconstitution ◽  
Γδ T Cells ◽  
Unrelated Donor ◽  
Γδt Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact

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&lt;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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