scholarly journals Aberrant Peripheral Immune Function in a Good Syndrome Patient

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xian Chen ◽  
Jie-xin Zhang ◽  
Wen-wen Shang ◽  
Wei-ping Xie ◽  
Shu-xian Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Status ◽  
Chronic Diarrhea ◽  
Respiratory Infections ◽  
Ex Vivo ◽  
Treg Cells ◽  
Recurrent Respiratory Infections ◽  
Interleukin 17A ◽  
Healthy Control ◽  
Normal Percentage

Good’s syndrome (GS) is often accompanied by recurrent respiratory infections and chronic diarrhea. The main purpose was to evaluate the peripheral immune status of a GS patient after thymoma resection. Twenty healthy volunteers were recruited as healthy controls (HCs). Flow cytometry was applied to determine the proportions of circuiting CD4+ T cells, CD8+ T cells, γδT cells, and regulatory T (Treg) cells in our GS patient. We also examined the proliferation capability of ex vivo CD4+ T cells and detected the levels of cytokines interferon- (IFN-) γ and interleukin-17A secreted by ex vivo immune cells from this GS patient. Compared with healthy control subjects, this GS patient had fewer B cells, an inverted ratio of CD4+/CD8+ cells, and more Treg cells in his peripheral blood. Additionally, the patient’s Vδ2 T cell levels were significantly decreased despite having a normal percentage of γδT cells. Ex vivo peripheral CD4+ T cells from the patient showed insufficient proliferation and division potential as well as excessive expression of PD-1. Moreover, IFN-γ was predominantly derived from CD8+ T cells in this GS patient, rather than from CD4+ T cells and γδT cells. This GS patient had impaired T and B cell immunological alternations and cytokine disruptions after thymectomy. Detailed research should focus on therapies that can adjust the immune status in such patients for a better outcome.

scholarly journals FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4953-4960 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Aloisio Felipe-Silva ◽  
Bianca Heemskerk ◽  
Daniel J. Powell ◽  
John R. Wunderlich ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Metastatic Melanoma ◽  
Treg Cell ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Production Capacity ◽  
Biological Marker ◽  
Foxp3 Expression ◽  
Treg Cells

Abstract Regulatory T (Treg) cells are often found in human tumors; however, their functional characteristics have been difficult to evaluate due to low cell numbers and the inability to adequately distinguish between activated and Treg cell populations. Using a novel approach, we examined the intracellular cytokine production capacity of tumor-infiltrating T cells in the single-cell suspensions of enzymatically digested tumors to differentiate Treg cells from effector T cells. Similar to Treg cells in the peripheral blood of healthy individuals, tumor-infiltrating FOXP3+CD4 T cells, unlike FOXP3− T cells, were unable to produce IL-2 and IFN-γ upon ex vivo stimulation, indicating that FOXP3 expression is a valid biological marker for human Treg cells even in the tumor microenvironment. Accordingly, we enumerated FOXP3+CD4 Treg cells in intratumoral and peritumoral sections of metastatic melanoma tumors and found a significant increase in proportion of FOXP3+CD4 Treg cells in the intratumoral compared with peritumoral areas. Moreover, their frequencies were 3- to 5-fold higher in tumors than in peripheral blood from the same patients or healthy donors, respectively. These findings demonstrate that the tumor-infiltrating CD4 Treg cell population is accurately depicted by FOXP3 expression, they selectively accumulate in tumors, and their frequency in peripheral blood does not properly reflect tumor microenvironment.

TNFR25 Expression on CD4+CD25+ T Cells: Down Modulation of Regulatory Activity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3165-3165
Author(s):  
Vadim Deyev ◽  
Melinda Roskos ◽  
Robert B. Levy ◽  
Eckhard R. Podack
Keyword(s):  
T Cells ◽  
Cell Function ◽  
Ex Vivo ◽  
Cell Activity ◽  
Treg Cells ◽  
Regulatory Activity ◽  
T Regulatory Cell ◽  
Tnf Receptor Family ◽  
Receptor Family

Abstract TNFR25 (“DR3”) is a member of the TNF receptor family that is expressed by activated CD4+ and CD8+ T cells. To determine if activated CD4+CD25+ T cells also expressed this TNFR family molecule, B6 CD4+CD25+ T cells were stimulated with anti-CD3/CD28 coated beads (kind gift of Dr. B. Blazar, U. Minn.) and expanded for 3–4 days. TNFR25 expression was readily detected on CD4+CD25+ FoxP3+ T cells. Since other members of the TNF receptor family (GITR, OX40, 4–1BB) are known to influence T regulatory cell function, we investigated whether TNFR25 signaling can regulate CD4+CD25+ T cell activity. TNFR25 triggering in B6-wt T regulatory CD4+CD25+ cells with the recombinant TNFR25 ligand TL1A or agonistic anti-TNFR25 antibody (4C12) resulted in reduction of their ability to suppress anti-CD3 induced ex-vivo proliferation of CD4+CD25− cells. 4C12 mediated TNFR25 signaling also reduced B6-wt Treg mediated inhibition of peptide induced proliferation of OVA-specific B6 CD8+ (OT-I) cells. To further investigate a role for TNFR25 in Treg cell regulation, TNFR25 (full length) transgenic mice were generated and bred onto the BL/6 background. CD4+CD25+ cells from these TNFR25 tg mice were found to possess diminished T regulatory activity in vitro as determined by their diminished inability to regulate proliferation by B6-wt CD4+ and OT-I CD8+ T cells. To assess their in vivo regulatory activity, B6-wt and B6 TNFR25 tg Treg cells were examined for their ability to inhibit graft vs. host disease (GVHD) following allogeneic MHC class I/II mismatched BMT. In contrast to B6-wt Treg cells, TNFR25 tg Treg cells exhibited significantly diminished ability to regulate the onset of GVHD in vivo as assessed by weight loss and clinical symptoms. Using agonistic antibody, stimulation of TNFR25 on transgenic Treg cells was also found to effectively remove the ex-vivo regulatory activity expressed by this population. To exclude any possible direct co-stimulatory effects of 4C12 antibody on the responding proliferating cells, CD4+CD25−T cells from TNFR25 dominant negative transgenic mice were employed. 4C12 mab again abolished Treg cell inhibitory activity. The effect of TNFR25 agonists on T reg cell activity in vivo is being further investigated in both mouse models of GVHD and IBD diseases. Initial observations administering 4C12 post-allogeneic BMT together with B6-wt Treg cells indicate a reduction in their ability to regulate GVHD. In total, these studies identify TNFR25 as a new potential target for augmenting CD4+ and CD8+ responses by concomitant direct co-stimulation of effecter cells and inhibition of T regulatory cell function.

Ex Vivo Expanded T Regulatory (Treg) Cells Block Conversion of Mixed Chimeras To Complete Donor Chimerism.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5168-5168
Author(s):  
Marina Lesnikova ◽  
Alla Nikitine ◽  
Nicola Mason ◽  
Richard A. Nash ◽  
George E. Georges
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Treg Cells ◽  
Large Animal Model ◽  
Control Group ◽  
Large Animal ◽  
Not Given ◽  
Tolerance Mechanism ◽  
Donor Chimerism ◽  
Mixed Chimeras

Abstract A highly effective method to establish long-term, stable mixed hematopoietic chimerism was developed in the dog model. This involves nonmyeloablative allogeneic hematopoietic cell transplantation (HCT), consisting of 2 Gray (Gy) total body irradiation (TBI), dog leukocyte antigen (DLA)-identical marrow, and short-term post-grafting immunosuppression. We hypothesized that CD4+CD25+ Treg cells may be important regulators for the maintenance of cellular immune tolerance after allogeneic HCT. Previously, we showed in 8 mixed chimeras that naive donor lymphocyte infusion (DLI) did not change the level of donor chimerism. However, reconditioning mixed chimeras with 2 Gy TBI followed by DLI “breaks” tolerance and increases the level of donor chimerism. Seven mixed chimeras were reconditioned with 2 Gy TBI followed by DLI. Within 4 weeks after DLI, conversion to 100% donor chimerism was seen in 5 of 7 dogs and 2 dogs had a > 50% sustained increase in donor chimerism. Four recipients developed graft-versus host disease (GVHD). A control group of 3 mixed chimeras reconditioned with 2 Gy TBI without DLI had no change in donor chimerism. These results suggest that reconditioning with 2 Gy TBI followed by DLI can break the tolerance mechanism established in mixed chimeras. Next we asked if CD4+CD25+ Treg cells obtained from mixed chimeras before reconditioning could block the increase in donor chimerism following 2 Gy TBI and DLI. Peripheral blood mononuclear cells (PBMC) from 8 mixed chimeras were obtained by leukapheresis and cultured in bulk mixed leukocyte culture (MLC) with 3rd party DLA-mismatched, unrelated and irradiated CD34+ derived dendritic cells (10:1 responder: stimulator ratio) or PBMC (1:1). On day 4 of MLC, CD25+ cells were isolated by positive immunomagnetic selection. Next, artificial antigen presenting cells (aAPC, KT32) were added to expand the CD4+CD25+ Treg cells. The aAPC expressed Fcγ receptor CD32, canine CD86, and human IL-15, were loaded with the canine-specific mitogenic anti-CD3ε antibody 17.6F9 and irradiated prior to stimulation of CD4+CD25+ Treg. After 7 days, Treg were expanded a median of 23 (range, 8–36)-fold. Expanded CD4+CD25+ Treg were assessed for phenotype and in vitro function. The Treg cells were generated from 8 mixed chimeras and were infused back into the respective dogs (median dose 1× 107/kg) after reconditioning with 2 Gy TBI and immediately prior to DLI. In 6 of 8 dogs there was no change in the level of donor chimerism at 16–20 weeks follow-up; 2 dogs converted to complete donor chimerism within 6 weeks. Treatment with expanded Treg cells blocked conversion to complete donor chimerism after 2 Gy TBI +DLI in 6 of 8 dogs, compared with significant increases in donor chimerism for all 7 dogs after 2 Gy TBI +DLI not given Treg (p=.007). None of the 8 Treg recipient dogs developed GVHD, compared with 4 of 7 not given Treg, (p=0.02). A control group of 4 mixed chimeras were infused with expanded, non-Treg CD25− T cells. To this end, CD25+ T cells were immunomagneticaly depleted on day 4 of MLC. CD25− T cells were expanded with aAPC. Three of 4 dogs converted to the complete donor chimerism within 7 weeks after 2 Gy TBI, non-Treg and DLI. These results suggest that ex vivo expanded CD4+CD25+ Treg cells have in vivo function in a large animal model and can restore the tolerance mechanism in mixed chimeras that is broken by 2 Gy TBI and DLI.

scholarly journals Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3632-3638 ◽  
Author(s):  
Elena Gonzalez-Rey ◽  
Alejo Chorny ◽  
Amelia Fernandez-Martin ◽  
Doina Ganea ◽  
Mario Delgado
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Vasoactive Intestinal Peptide ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Treg Cells ◽  
Peripheral Tolerance ◽  
Blood Monocytes ◽  
Endogenous Factors ◽  
Tolerogenic Dcs

Induction of antigen-specific tolerance is critical for autoimmunity prevention and immune tolerance maintenance. In addition to their classical role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regulatory T (Treg) cells. The possibility of generating tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. Characterizing endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. We here report that the immunosuppressive neuropeptide vasoactive intestinal peptide (VIP) induces the generation of human tolerogenic DCs with the capacity to generate CD4 and CD8 Treg cells from their respective naive subsets. The presence of VIP during the early stages of DC differentiation from blood monocytes generates a population of IL-10-producing DCs unable to fully mature after the effects of inflammatory stimuli. CD4 Treg cells generated with VIP-differentiated DCs resemble the previously described Tr1 cells in terms of phenotype and cytokine profile. CD8 Treg cells generated with tolerogenic VIP DCs have increased numbers of IL-10-producing CD8+CD28--CTLA4+ T cells. CD4 and CD8 Treg cells primarily suppress antigen-specific TH1-mediated responses. Therefore, the possibility of generating or expanding ex vivo tolerogenic DCVIPs opens new therapeutic perspectives for treating autoimmune diseases and graft-versus-host disease after allogeneic transplantation in humans.

Overcoming Rejection of Bone Marrow Allografts by Treg Cells in a Stringent Mouse Model for T Cell Mediated Rejection: Tolerance Induction by Third Party “Off-the-Shelf” Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 576-576
Author(s):  
David Steiner ◽  
Noga Brunicki ◽  
Esther Bachar-Lustig ◽  
Yair Reisner
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Rejection ◽  
Ex Vivo ◽  
Tolerance Induction ◽  
Treg Cells ◽  
Third Party ◽  
Donor Type

Abstract Recent reports have shown that donor or host CD4+CD25+ Treg cells can be used to control GVHD or graft rejection following allogeneic BMT in mice. More recent data suggests that in the context of T cell depleted BM allografting, engraftment was only mildly improved by Treg cells alone, or by Rapamycin (RAPA) alone, but it was markedly enhanced by using Treg cells in conjunction with RAPA. These studies were carried out in a mouse model specifically designed to measure T cell mediated graft rejection. In this model, lethally irradiated (11Gy) C3H mice were infused with 1x104 purified host type T cells (HTC) and were transplanted one day later with 2x106 BM cells from Balb-Nude donors, which are markedly depleted of T cells and do not induce GVHD. Rejection mediated by the HTC is manifested by severe aplasia and lethality within 21 days posttransplant. In 10 independent experiments none of the mice in the irradiation control survived (0/62), the majority of the mice receiving BM survived (58/63) while marked rejection, associated with poor survival (2/62) was found in the group receiving purified HTC prior to the BM transplant. In the present study we further tested in this model whether third party Treg cells could be used instead of donor or host Treg cells to overcome rejection of BM allografts. We initially tested freshly isolated lymph node CD4+CD25+ cells. C3H (H2k) recipients received BM from Balb- Nude (H2d) donors and the Treg cells were obtained from Balb/c or FVB (H2q) donors. As in our previous study, while none of the recipients survived upon treatment with RAPA alone, using third party or donor type Treg cells in conjunction with RAPA led to survival of 9 of 13 and 7 of 10 mice respectively. Thus, the third party fresh Treg cells were as effective as the donor type cells in preventing graft rejection (P>0.05). Considering the low levels of CD4+CD25+ cells in peripheral blood or spleen, new strategies for growing these cells ex-vivo have been developed. Although, Treg cells exhibit low proliferative potential in-vitro upon TCR stimulation, the feasibility of growing mouse or human regulatory cells has been demonstrated mainly using the combination of TCR stimulation (either with an anti-TCR antibody or with allogeneic stimulator cells), costimulatory signals and high doses of IL-2. When tested in the same model, Treg cells ex-vivo expanded by stimulation against 4th party allogeneic cells, exhibited effective enhancement of engraftment of Balb-Nude BM. Thus, in four independent experiments, when assessing treatment with expanded Treg cells, of third party or donor type origin, the survival rate was 19 of 35 (54%) and 25 of 40 (62%) mice, respectively. Again, in both instances the marked potential of Treg cells to overcome T cell mediated rejection was exhibited only when co-administered with RAPA. In conclusion, our data strongly indicate that, at least in the bone marrow transplantation setting, third party Treg cells could afford a new viable ‘off-the-shelf’ source for tolerance induction. The use of third party Treg cells in contrast to donor type cells could allow advanced preparation of a large bank of Treg cells, with all the appropriate quality controls required for cell therapy. Further studies with human Treg cells in-vitro are required to ascertain the potential of third party cells as a valuable source for clinical transplantation.

Cellular immunity of patients with malignant glioma: prerequisites for dendritic cell vaccination immunotherapy

2006 ◽  
Vol 105 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Marion Rapp ◽  
Zakir Özcan ◽  
Hans-Jakob Steiger ◽  
Peter Wernet ◽  
Michael C. Sabel ◽  
...  
Keyword(s):  
T Cells ◽  
Blood Cell ◽  
White Blood Cell ◽  
Cellular Immunity ◽  
Immune Status ◽  
Ex Vivo ◽  
Serum Free Medium ◽  
Free Medium ◽  
Serum Free ◽  
Hla Dr

Object Vaccination therapy that uses dendritic cells (DCs) is a promising immunotherapeutic approach. However, it relies on intact cellular immunity and efficient generation of mature DCs, both of which can be impaired in patients with glioma. Therefore, the immune status and ex vivo generation of DC in such patients were studied. Methods The frequencies of white blood cell subsets and monocyte-derived, mature DCs in patients with high-grade gliomas and healthy control volunteers were analyzed using flow cytometry. In the patients, frequencies of lymphocytes, T cells, and B cells were reduced in comparison with the volunteers in the control group, whereas frequencies of neutrophils and monocytes were increased. There were no differences between the two groups in terms of white blood cell counts or the frequency of NK cells and the major T-cell subsets. The responsiveness of T cells to lectin stimulation was normal. For monocytes, lower frequencies of CD80+ and CD86+ cells but not of CD40+ and HLA-DR+ cells were observed in patients. Ex vivo DC generation in a two-step culture protocol in autologous plasma–supplemented medium or in serum-free medium showed only minor differences in CD80 and HLA-DR expression between the patient and control groups. Frequencies of CD83+, CD1a+, CD14−, CD40+, and CD86+ cells were comparable. Overall, the serum-free medium was superior to the plasma-supplemented medium and allowed efficient ex vivo generation of CD83+, CD1a+, and CD14− mature DCs. Conclusions Only minor defects in the immune status of patients with glioma were observed, which probably would not hamper immunotherapy. Mature DCs can be generated successfully in normal numbers and with typical immunophenotypes from monocytes of patients with glioma, particularly under serum-free conditions.

scholarly journals Low frequency of GITR+ T cells in ex vivo and in vitro expanded Treg cells from type 1 diabetic patients

2013 ◽  
Vol 25 (10) ◽  
pp. 563-574 ◽  
Author(s):  
Cristina Xufré ◽  
Manuela Costa ◽  
Carme Roura-Mir ◽  
Eva Codina-Busqueta ◽  
Lorena Usero ◽  
...  
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Low Frequency ◽  
Treg Cells ◽  
Diabetic Patients ◽  
Type 1 Diabetic Patients

scholarly journals Plasticity of Treg and imbalance of Treg/Th17 cells in patients with systemic sclerosis modified by FK506

2021 ◽  
Vol 35 ◽  
pp. 205873842199808
Author(s):  
Xinjuan Liu ◽  
Yu Wu ◽  
Mengtao Li ◽  
Jianyu Hao ◽  
Qian Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Systemic Sclerosis ◽  
Th17 Cells ◽  
Treg Cells ◽  
Proliferation Capacity ◽  
Healthy Control ◽  
Immune Imbalance

To determine the effects of Tacrolimus (FK506) on Treg cells and subpopulations in SSc patients and assess the ability of FK506 to modify the immune imbalance of Treg/Th17 cells. We analyzed PBMC from five SSc patients and six healthy control by flow cytometry after cultured with 0, 0.1, 1, or 10 ng/ml FK506 in vitro. The number of Treg cells decreased in SSc patients treated with FK506. The number of FrI cells were decreased in SSc following FK506 treatment. The drug did increase the frequency of FrII/Treg cells, but not FrII cells. However, FK506 significantly decreased FrIII in both SSc patients and controls. FK506 clearly decreased the numbers of Th17 cells and FoxP3+IL-17+ cells. The proliferation capacity of cells was also inhibited by FK506, which had a greater effect on FoxP3− cells than FoxP3+ cells. FK506 did inhibit the proliferation of FrIII cells, but not FrI or FrII cells. Our study provides that FK506 reduced the number of FoxP3low CD45RA− T cells (FrIII) by inhibiting its proliferation. Therefore, FK506 modifies Treg cells and the immune imbalance between Tregs and Th17 cells in SSc patients.

scholarly journals Regulatory T Cells for Acute Graft Versus Host Disease Prevention

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-8
Author(s):  
Seren Durer ◽  
Ceren Durer ◽  
Gilles Jad Hoilat ◽  
Veli Bakalov ◽  
Bhaskara Reddy Madhira ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Phase I ◽  
Phase Ii Study ◽  
Ex Vivo ◽  
K562 Cells ◽  
Treg Cells ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Historical Controls

BACKGROUND GVHD remains a major cause of morbidity and mortality after allo HSCT. The past few years have shown a number of successful advances in cellular therapies for the treatment of hematologic malignancies. It is logical to expand the use of these therapies earlier, in strategies aimed at prevention. Several studies showed that regulatory T cells (Treg) can reduce the incidence of aGVHD. METHODS Studies were identified using electronic databases (Medline, Embase, and Cochrane). Preclinical studies were excluded. Data analysis was performed using GraphPad Software 8.4.2. RESULTS 160 patients were identified from 7 clinical studies. 85% of the patients had acute leukemia and were in complete remission at the time of transplant. Tregs were isolated from either UCB or PB. Tregs were expanded ex-vivo using IL-2, CD3/CD28 ab coated beads and K562 cells in three studies (n=40). 1.Ex-vivo expanded Treg: In a phase I study (Brunstein et al) of UCB-derived Tregs in 23 pts undergoing double umbilical cord transplantation, Tregs were cultured with antiCD3/anti CD28 and IL-2. Ex-vivo expanded Tregs were given on day+1 and day+15. Eighteen pts received Treg cells at dose of >3x106 cells/kg. Grade II-IV aGvHD was seen in 39% of pts who received ≥3x106 cells/kg vs 43% in historical controls. In this study, CsA+MMF or sirolimus+MMF were used for GvHD prophylaxis. In a follow up study of 11 patients, Tregs were markedly expanded using K562 cells. Higher Treg doses were achieved up to 100x106cells/kg and the median proportion of CD4+CD127-FOXP3+ within the infused products was 87%. Grade II-IV aGVHD was 9% at 100 days vs 45% in control group. Treg cells were not detected in the peripheral blood after 14 days of infusion. In a phase II study (Kellner et al; Zeng et al), three of six pts undergoing PB MUD received ex-vivo expanded UCB-derived Tregs 1x106/kg at day-1. All developed aGVHD due to the high donor Tcon cells in the graft with donor Tcon:UCB Treg ratio as high as 356:1. Sixth patient was given 1x107 cells/kg Tregs in the presence of anti CD3/28 microbeads and IL-2 with Treg:Tcon ratio of 1:40. No aGVHD was observed in this patient compared to the others who received Treg at the dose of 1x106cells/kg. 2.Unexpanded Treg: In a study (Di Ianni et al) involving 26 high risk leukemia pts undergoing haplo-transplant with TBI based conditioning, 21 pts were infused with donor Tregs at a dose of 2x106 cells/kg and five pts were infused with Treg at a dose of 4x106 cells/kg on day -4, followed by Tcon infusion ranging from 0.5x106 to 2x106 cells/kg on day 0. No post-transplant immune suppression was given. Grade II-IV aGVHD was observed in 2 out of 26 patients who received 4x106cells/kg Tregs and 2x 106cells/kg Tcons. No GVHD was observed in pts who received 2x106cells/kg Tregs followed by 0.5-1x106 cells/kg Tcons. A phase II study by the same group (Martelli et al) reported on an additional 17 pts who received Tregs (2x106cells/kg) at day-4 co-infused with Tcon (1x106cells/kg) at day 0. Six of 41 (15%) evaluable pts developed grade II-IV aGVHD (vs 11% in historical cohort) with two pts requiring a short course of immunosuppression. Incidence of relapse was lower in Treg group than historical controls (5% vs 21%). In a phase I/II study (Meyer et al), 12 pts with hematological malignancies who underwent HLA-matched transplantation received purified Tregs (1-3x106cells/kg) on day0 followed by Tcon (1-3x106cells/kg) on day+2. GVHD was seen in 80% of pts with 50% being grade III in pts who received frozen Tregs. Upon revising protocol, 7 pts were given fresh Treg. The patients also received either tacrolimus or sirolimus for immunosuppression. None of 7 pts in revised cohort developed GVHD. Recent study applied hyper-fractionated TBI to the conditioning regimen in 12 pts out of 40 to further reduce leukemia relapse in Treg/Tcon based haplo-HSCT. Treg was administered at the dose of 2x106cells/kg and Tcon at 1x106cells/kg. No post-transplant GvHD prophylaxis was given. Grade II-IV aGVHD was observed in 12 pts. CONCLUSION These studies suggest that Treg therapy may represent an effective prevention strategy against acute GvHD (figure 1). Stimulated Treg expansion strategies and higher doses of Treg appear to be associated with lower incidence of aGVHD. Treg infusion was well-tolerated without serious adverse events. Large prospective clinical trials are warranted in order to establish the optimal infusion dose, optimal expansion strategies and dosing schedule. Disclosures No relevant conflicts of interest to declare.

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