Plasma Levels of Soluble Interleukin-7 Receptor Alpha (sIL-7Ra) and IL-7Ra Polymorphism After Allogeneic Stemcell Transplantation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4012-4012 ◽  
Author(s):  
Zaiba Shamim ◽  
Stephanie Thiant ◽  
Sylvie Faucher ◽  
Bachra Choufi ◽  
Lars Ryder ◽  
...  
Keyword(s):  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
Elevated Serum ◽  
Biological Significance ◽  
Soluble Form ◽  
Healthy Individuals ◽  
Related Factors ◽  
Post Transplant ◽  
Interleukin 7 ◽  
Baseline Values

Abstract Abstract 4012 Background: Interleukin-7 (IL-7) is a cytokine essential for T cell development in the thymus and maintenance of peripheral T cells. IL-7 binds to cellular IL-7 receptors (IL-7Ra-common g chain heterodimer), in competition with a soluble form of the receptor, shed by the cells (sIL-7Ra). We have identified single nucleotide polymorphisms in the exons of the gene encoding IL-7Ra (+510T/C rs1494558, +1237 G/C rs1494555, 2087 C/T rs6897932), and previous results by us and by others indicate that IL-7R SNPs are associated with aGvHD and mortality after SCT. Moreover, the biological significance of +2087 C/T SNP has been suggested by the finding of elevated serum levels of sIL-7Ra in healthy individuals with 2087CC (Haplotype 4), also associated with increased alternative splicing of exon 6 and a higher frequency of recent thymic emigrants. We hypothesized that sIL-7Ra levels during SCT are influenced by genetic polymorphism and may play a role in immune reconstitution after SCT. Aims: 1) To investigate sIL-7Ra levels during SCT along with IL-7Ra genotypes and 2) to evaluate associations between sIL-7Ra levels and immune reconstitution and outcome in SCT. Patients and Methods: 122 patients undergoing SCT for haematological malignancies after either myeloablative (n= 52) or reduced intensity conditioning (n=70) were included. Donors were either matched siblings (n=68) or matched unrelated donors (n=54), and the patient age at the time of transplant was 50 years (6–67) (median (range)). sIL-7Ra levels were measured in plasma by a quantitative bead capture assay. IL-7Ra SNPs were determined by a SSP-PCR system and IL-7 was tested by ELISA (R&D) (n=77). Results: sIL-7Ra levels decreased during the course of transplantation from 113 ng/ml (32–558) at day −15 to 48 ng/ml (32–195) at day +14 (p=0.0001), and reached baseline levels again at day +60. sIL-7Ra levels were not associated with the intensity of the conditioning regimen. This pattern appeared to be inversely mirrored by the IL-7 levels, which increased from baseline values at day –14 of 2.4 pg/ml (0.3–17.6) to 11.3 pg/ml (2.0–30.2) (p<0.0001) at day +14, followed by a gradual decline down to baseline values at day +60. sIL-7Ra levels at day +90 were reduced in patients transplanted with donors carrying IL-7Ra 2087T allele, in line with our previous findings in healthy individuals (105 ng/ml (42–274) vs. 152 ng/ml (20–971), p=0.0015). In addition, post-transplant sIL-7Ra levels correlated with pre-transplant sIL-7Ra levels (r=0.39 p=0.0032), indicating that patient related factors in addition to the genotype of the donor lymphocytes may play a role in the regulation of sIL-7Ra levels post-transplant. sIL-7Ra appeared to be predictive of the rate of immune reconstitution by the finding that sIL-7Ra at day +14 correlated significantly with total lymphocyte counts post-transplant (day +90: r=0.28 (p=0.031) and day +180: r=0.55 (p<0.0001)). In contrast, IL-7Ra genotypes were not associated with immune lymphocyte counts post-transplant and early post-transplant IL-7 levels did not correlate significantly with lymphocyte counts at any stage. Outcomes: There was a trend towards an association between high sIL-7Ra levels and increased overall survival (p=0.057), but sIL-7Ra levels were unrelated to the occurrence of aGvHD. However, the IL-7/sIL-7Ra ratio at day +14 was significantly higher in patients with grade 2–4 aGvHD compared to grade 0–1 aGvHD (0.29 (0.04–0.73) vs 0.19 (0.01–0.8), p=0.033). Conclusion: The data of the present study indicates that sIL-7Ra levels after SCT are determined by the IL-7R 2087 genotype of the donor in addition to patient related factors. sIL-7Ra levels in the early phase post transplant is associated with the rate of lymphocyte recovery post-SCT. Thereby this study adds to the growing evidence suggesting the importance of the IL-7 axis in SCT. The study further suggests that monitoring sIL-7Ra levels post-transplant may help to guide the clinical use of IL-7. Disclosures: No relevant conflicts of interest to declare.

scholarly journals First Results of a Prospective I/II Clinical Trial in Adult Patients Using TCR Alpha/Beta Depleted Stem Cell Transplantation from Matched Related and Unrelated Donors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2164-2164
Author(s):  
Moniek De Witte ◽  
Anna Van Rhenen ◽  
Geerte Van Sluis ◽  
Rick Admiraal ◽  
Lotte van der Wagen ◽  
...  
Keyword(s):  
Research Funding ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Post Transplant ◽  
Kaplan Meier ◽  
Unrelated Donors ◽  
Male Patients ◽  
Grade Iii

Abstract Introduction: We report the first analysis of a multicenter prospective single-arm phase I/II study that assesses the safety and feasibility of transplantation of TCRalpha/beta depleted stem cells from matched related or unrelated donors using the CliniMACS plus System (Miltenyi Biotec, Germany) in combination with a non-myeloablative conditioning in adult patients (trial nr NL48606.000.14). The conditioning regimen consisted of ATG (Thymoglobulin®) 1.5mg/kg i.v. days -12 to -9; fludarabine i.v. 40 mg/m2 days -5 to -2 and busulfan i.v. (Busivex®) days -5 to -2 (cumulative AUC of 80-90mg*h/L), followed by 28 days of mycophenolic acid. All 35 subjects were eligible to address the primary endpoint which is the incidence of acute GVHD at day 100. Results: 2 centers enrolled 10 female and 25 male patients (median age 59 years, range 19 - 69 years), including 9 AML, 4 ALL, 2 CML, 5 MM, 1 NHL, 10 MDS, 4 MPN. Diseases were in CR (n=17), VGPR (n=1), PR (n=5) or non-remission (n=12). 4 subjects had one or more previous allogeneic SCTs. Donors included 4 MRD, 24 10/10 matched MUD and 7 9/10 matched MUD. 8 male patients received stem cells of female donors. The median number of CD34+ cells and αβ TCR cells/kg was 6.1x 10^6 (range, 1.9-10) and 14.5x10^3 (range, 0-136), respectively. One primary graft failure was observed. Primary engraftment of ANCs > 500 cells/μL was reached at a median of 14 days (range 9 - 48 days) and of platelets > 20 at a median of 17 days (range 10 - 99) days. The median time of follow-up of this first analysis was 190 days (range 110-400 days). 3/35 patients developed acute GVHD grade III-IV during the first 100 days, 9/35 patients developed acute GVHD grade II-IV and 16/35 patients grade I-IV at day 100. At day 100 the cumulative incidence (CI) of CMV was 31%, of EBV 36% and of BK cystitis 20%. The combined CI of CMV/EBV/BK infections with a CTC-AE grade III-V was 53% at day 100. Immune reconstitution was rapid with a median of 227 (range 34 - 1626) CD3+ cells/µl on day 100 but varied substantially between patients. The median numbers of CD3/CD4+ and CD3/CD8+ at day 100 post transplant were 60 (range 30 - 120) and 124 (range 5 - 1450) cells/µl. The median numbers of NK were 289 (range 32-1140) at day 30 and 128 (range 24 - 1228) cells/µl at day 100 post transplant. The median numbers of γδ T cells were 38 (range 4-143) at day 30 and 50 (range 8-556) cells/µl at day 100 post transplant. 26 out of 35 patients were alive, 2 patients died of a relapse, 2 of GVHD and 5 of infectious complications. Kaplan Meier estimates of the OS are 88% (+/- 6%) at day 100 and 68% (+/- 9%) at 1Y. Kaplan Meier estimates of the EFS are 77% (+/- 7%) at day 100 and 52% (+/- 10%) at 1Y. 2 patients developed a relapse before day 100 and 5 patients before 1Y. It is noted that the outcome of 5 patients with MM was very poor in this cohort (3 patients developed a relapse and 2 patients died of complications). Conclusion: Allo-SCT of αβ T cell depleted PBMCs form matched related or unrelated donors, in combination with early ATG and a non-myeloablative conditioning regimen, resulted in favorable rates of primary engraftment (34/35), a CI of aGVHD II-IV of 26% with only minimal immuno-suppression and an encouraging early disease control (Fig 1). OS survival was mainly impacted by NRM (Fig 1), by which the majority of complications were of infectious nature. While all patients with MM suffered from NRM or relapse, all other disease categories had a rather favorable outcome. Reducing inter-individual variations in immune reconstitution early after transplantation will be key to further improve outcomes. Disclosures Minnema: Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Servier: Consultancy. Kuball:Novartis: Research Funding; Miltenyi Biotec: Research Funding; Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gd T cells and receptors and isolation strategies, Research Funding.

Rapid Immune Reconstitution Following Unmanipulated Haploidentical BMT with Post-Transplant High Dose Cyclophosphamide

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3050-3050 ◽  
Author(s):  
Alida Dominietto ◽  
Anna Maria Raiola ◽  
Barbara Bruno ◽  
Maria Teresa van Lint ◽  
Francesco Frassoni ◽  
...  
Keyword(s):  
Immune Reconstitution ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cd4 Counts ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Donor Type ◽  
Unrelated Cord Blood

Abstract Abstract 3050 Background. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for the majority of hematological malignancies. Early and successful immunologic reconstitution after HSCT reduces morbidity and mortality due to infection complications and improves survival. Aim of the study. We analyzed immune recovery after HSCT in 444 patients according to donor source. Patients and Methods. From January 2005 to June 2011 176 patients were grafted from HLA identical siblings (MSD), 125 from alternative donors (1 antigen mismatched family or unrelated donors) (ALT), 103 from unrelated cord blood grafted intra bone (CBIB) and 40 from haplo-identical mismatched family donors (HAPLO). All patients received unmanipulated bone marrow: 283 after a myeloablative (MA) conditioning regimen (CY-TBI or BU-CY) and 161 after a fludarabine based reduced intensity regimen (RIC). Graft versus host disease (GvHD) prophylaxis was cyclosporin methotrexate (CyA+MTX) for all patients except for CBIB (CyA and mycophenolate, MMF) and for HAPLO transplants which consisted of CyA+MMF and post-transplant high dose cyclophosphamide (HDCY) according to the Baltimore protocol (Lutznik et al BBMT 2008). Anti-thymocyte globulin (ATG) was used only for ALT transplants. Results. We compared immune reconstitution in MA and RIC transplants according to donor type at different time points post BMT. CD3+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 477, 565, 700; in ALT donors were 146, 404, 470; in CBIB were 30, 57, 196; for HAPLO transplants they were 195, 182, 499. CD3+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 301, 660, 700; in ALT donors were 506, 186, 721; in CBIB 234, 399, 522; in HAPLO were 178, 276, 1300. CD4+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 166, 170, 198; in ALT donors were 36, 86, 111; in CBIB 7, 36, 106; for HAPLO transplants they were 45, 127, 211. CD4+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 89, 189, 274; in ALT donors were 131, 210, 220; in CBIB 52, 110, 130; for HAPLO transplants they were 41, 205, 385. CD8+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 280, 389, 500; in ALT donors were 102, 278, 413; in CBIB 42, 16, 51; in HAPLO transplants were 73, 424, 408. CD8+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 196, 432, 300; in ALT donors were 366, 65, 494; in CBIB 71, 167, 199; for HAPLO transplants they were 137, 129, 900. CD3, CD8, and CD4 counts in HAPLO transplants were not statistically different from MSD with the only exception of day +30, both for MA and RIC conditioning. Platelet median counts/μl on day+30, +90, +180 in MA conditioning were in MSD 142, 129, 180, in ALT 75, 101, 147, in CBIB were 19, 77, 128 and for HAPLO transplants were 67, 126, 128; in RIC conditioning platelets counts were in MSD 137, 156, 168, in ALT 33, 134, 142, in HAPLO were 77, 95, 188. Acute GvHD II-IV developed in 29% (MSD) 38% (ALT) 16% (CBIB) and 12% (HAPLO) (p=0.004) in MA conditioning and 40% (MSD) 18% (ALT) 25% (CBIB) and 10% (HAPLO) (p=0.07). Overall Cumulative Incidence of Non-Relapse Mortality (CI-NRM) was respectively 18% (MSD), 35% (ALT), 34% (CBIB), 22% (HAPLO) (p=0.02) in MA conditioning (p=0.02) and was 30% (MSD), 33% (ALT), 45% (CBIB), 0% (HAPLO) (p=0.02) in RIC conditioning (p=0.02). Day+100 CI-NRM was respectively 10% (MSD), 21% (ALT), 19% (CBIB), 12% (HAPLO) in MA conditioning (p=0.01) and 11% (MSD), 19% (ALT), 26% (CBIB), 0% (HAPLO) in RIC conditioning (p=0.02). Death due to infections were respectively 6% (MSD), 26% (ALT), 30% (IBCB), 17% (HAPLO) in MA conditioning and for RIC were 15 (MSD), 36% (ALT), 32% (IBCB), 0% (HAPLO). Conclusions. HAPLO transplant with HDCY post transplant as proposed by the Baltimore group, is associated with (1) rapid immunologic (CD3, CD4, CD8) recovery (2) low infectious death rate, (3) low overall and Day+100 CI-NRM, (4) rapid hematologic recovery. These results are comparable with those achieved with MSD and warrant further studies with HDCY post transplant as a GvHD prophylaxis. Figure: absolute CD4+ counts/μl on day+30, +90, +180, according to donor type in MA conditioning regimen. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Post-Transplant Cyclophosphamide (PTCY) Vs Anti-Thymoglobulin (ATG) As Part of the Gvhd Prophylaxis for Fludarabine/Clofarabine/Busulfan Reduced Intensity Conditioning (RIC) in Allogeneic Stem Cell Transplantation (allo-SCT): Influence on Early Immune Reconstitution

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1955-1955
Author(s):  
Christelle Retiere ◽  
Catherine Willem ◽  
Thierry Guillaume ◽  
Henri Vié ◽  
Laetitia Gautrot-Rolland ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
Immune Recovery ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
The Impact

Abstract Introduction: The influence of PTCY on early immune reconstitution after allo-SCT has been poorly studied so far, especially in comparison to standard use of ATG as GVHD prophylaxis. Patients and Methods: A prospective study was conducted at the CHU of Nantes with the aim to compare early immune recovery between patients receiving PTCY or ATG as GVHD prophylaxis after a RIC allo-SCT. Secondary objectives were to study the impact of 1 vs 2 days of PTCY (CY1 vs CY2) or ATG (A1 vs A2), and of fludarabine (Flu) vs clofarabine (Clo) as part of the RIC regimen. As such, 3 RIC regimens were considered in both groups: FluCY2 (Baltimore regimen, Luznic, BBMT 2008), FluCY1, CloCY2 (where Clo replaces Flu), on one hand, and FluB2A2, CloB2A2, CloB2A1 (Chevallier, Haematologica, 2014), on the other hand. FluCY2 and FluB2A2 are currently standard of care RIC regimens for patients with haplo-identical and matched donors, respectively. Five patients had to be included in each RIC subgroup, depending on the type of disease and donor (/): FB2A2 (lymphoid/matched); FluCY2 (lymphoid/haplo); CloB2A2 or CloB2A1 (myeloid/matched); CloCY2 (myeloid/haplo), FluCY1 (myeloid or lymphoid/matched). The source of graft was peripheral blood stem cells for all cases. Blood samples were collected before starting the conditioning regimen then 3 times per week from day +0 until day+30, and at days +60 and +90. The following cell subsets were studied: a/b and g/d CD3+, CD8+ and regulatory (Tregs) T cells, B and NK cells and monocytes. The median percentage (%) compared to total lymphocytes was considered for all lymphocytes subsets between days 0-30. Thereafter, median absolute numbers (AN)/mm3 were considered for samples collected at days +30, +60 and +90. The study was approved by the IRB of the CHU of Nantes and all patients provided informed consent. Results: Between August 2014 and May 2015, thirty patients were included, including 15 in both groups and 5 in each RIC subgroups. Median age was 61 years. There were more patients with active disease at transplant (47% vs 7%) and more haplo-identical donors (67% vs 0%) in the PTCY group. All patients engrafted and were alive at day +90. However, 1 PTCY patient with T-ALL relapsed before day+100. Within the first month post-transplant, PTCY group had a significantly higher median % of a/b T cells (69.1 vs 18.9, p<0.0001) and Tregs (3.46 vs 0.45, p<0.0001) while ATG group had higher median % of NK (23 vs 2.57, p<0.0001) and B-cells (0.88 vs 0.43, p=0.0002). Between day+30 and day+90, ATG group had significant higher median counts of a/b T cells at days +60 (1316 vs 79.6, p=0.0001) and +90 (795.8 vs 151.6, p=0.03); g/d T cells at day+60 (27.6 vs 1.26, p=0.002); CD8 T cells at day+60 (735 vs 29.6, p=0.008); NK cells at day+30 (203.7 vs 89, p=0.04) and monocytes at days +30 (455.5 vs 221.7, p=0.009) and +60 (832.5 vs 247.2, p=0.004). Compared to the standard FluCY2 regimen, although not significant, FluCY1 was associated with higher median %, between days 0-30 of g/d T cells (2.32 vs 0.8) and higher median AN of g/d T cells at days +30 (9.2 vs 1.02) and +60 (9.22 vs 1.05), of B cells at days +30 (0.4 vs 0.14) and +60 (1.6 vs 0.39) and of NK cells at day+30 (213.9 vs 82.7). Compared to the standard FB2A2 regimen, although not always significant, CloB2A1 was associated with higher median % between days 0-30 of Tregs (0.97 vs 0.25, p=0.002) and higher median AN of g/d T cells at day+30 (6.8 vs 2), B cells at days +30 (2.35 vs 0) and +60 (43.7 vs 0.19), NK cells at day +30 (288 vs 62.1) and Tregs at days +30 (4.3 vs 0.2), +60 (8.8 vs 1.14) and +90 (8.96 vs 3.45). Compared to the standard FB2A2 regimen, although not always significant, CloB2A2 was associated with higher median % between days 0-30 of a/b T cells (28.87 vs 3.78, p=0.01) and B cells (0.76 vs 0.5, p=0.02) and higher median AN of a/b T cells at days +30 (324.3 vs 125.8) and +90 (1594 vs 604.3), of g/d T cells at day +30 (7.35 vs 2), of CD8 + T cells at days +30 (209.7 vs 38.9) and +90 (1211.7 vs 504.6), of B cells at day +30 ( 1.41 vs 0), of NK cells at days +30 (303 vs 62.1), +60 (514.5 vs 225.7) and +90 (647 vs 102.8, p=0.03) and of monocytes at days +30 (688.9 vs 257.4, p=0.03) and +90 (2157.4 vs 611.2). Conclusion: Strong differences exist in term of early immune recovery when using PTCY or ATG as part of the GHVD prophylaxis for RIC allo-SCT. Dose or drug modifications within the standard RIC regimen in both groups may be envisaged to favor some cell population recoveries after allo-SCT in order to increase outcome in patients. Disclosures No relevant conflicts of interest to declare.

Toll-Like-Receptor Expression and Cellular Immune Reconstitution In AML-Patients with Elevated Serum Ferritin Levels After Allogeneic transplant.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1049-1049 ◽  
Author(s):  
Ahmet Elmaagacli ◽  
Nina Steckel ◽  
Michael Koldehoff ◽  
Sandra Christoph ◽  
Hellmut Ottinger ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Innate Immune System ◽  
Immune Reconstitution ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Elevated Serum ◽  
Innate Immune ◽  
Tlr9 Expression ◽  
Post Transplant ◽  
Cellular Immune

Abstract Abstract 1049 Elevated pretransplant serum ferritin levels have been associated with an increased susceptibility for opportunistic infections and increased incidence of morbidity and mortality after allogeneic haematopoietic stem cell transplantation (HCT). We studied in 81 patients who underwent myeloablative allogeneic HCT for acute myeloid leukemia pre- and posttransplant serum ferritin levels and correlated the serum ferritin levels with the TLR9 expression and the cellular immune reconstitution 3 and 12 months post transplant. Further, we studied in vitro-experiments in Kasumi-1 cells the TLR1, TLR2, TLR3, TLR5, TLR7, TLR9 and TLR10 expression after overwhelming iron and ferritin exposure. The average pretransplant serum ferritin level was 1245 μg/ml (mean) in all AML-patients (mean 1100μg/l for patients with AML in 1.CR and mean 1820μg/l for patients with AML > 1.CR). Post transplant serum ferritin level increased up to 2080 μg/ml (mean) for all AML patients (mean 1290mg/l for AML in 1.CR and mean 2350 μg/l for patients with AML > 1.CR). The application of 300ng iron to acute leukaemia cell lines SD1, and Kasumi-1 cells increased significantly TLR1, TLR2, TLR3, TLR5, TLR7 and TLR9 expression in relation to the housekeeping gene abl measured by real-time RT-PCR. In Kasumi-1 cells TLR1 increased up to 50,6% (p=0.014) TLR2 up to 35.5% (p=0.046), TLR3 up to 57,8% (p=0.006), TLR5 up to 62.9% (p=0.005), TLR7 up to 46.2% (p=0.02), TLR9 up to 44.2%(p=0.026) and TLR10 up to 54,7% (p=0.07) compared to untreated Kasumi-1 cells. The application of 2000μg/L ferritin increased TLR9 expression even more extensively in Kasumi-1 cells: TLR1 increased up to 332% (p<0.001), TLR2 up to 150% (p=0.016), TLR3 up to 293% (p<0.0001), TLR5 up to 349% (p<0.0001), TLR7 up to 287% (p<0.0001), TLR9 up to 229% (p=0.028). Elevated TLR-expression was also seen in CD34+ progenitor cells derived from volunteers. Further, patients with elevated post transplant ferritin level > 2000 μg/l had an increased TLR9 expression in mononuclear cells (TLR9/ABL quotient 6485 versus 4543; p<0.05) 3 months post transplant. The numbers of T helper cells (mean 412 versus 231 cells/μl 3 months post transplant, p=0.014), and cytotoxic T cells CD4+CD8+ in patients with elevated serum ferritin level were significantly elevated after transplant (mean 285 versus 164 cells/μl 3 months post transplant, p=0.027), whereas no differences were found in the number of B19+ cells and Nk cells. These results indicate that elevated ferritin levels might activate the innate immune system by increasing TLR expression. This might be of importance since we recently showed that increased TLR9 expression was associated with adverse impact on non-relapse mortality in the transplant setting. Further exaggerated TLR9 expression has been discussed to induce overwhelming immune responses as SIRS or ARDS. More studies are definitely necessary to evaluate the role of elevated iron overload on the innate immune system. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immune Reconstitution in 107 Children with Sickle Cell Anemia Transplanted with Bone Marrow or Cord Blood from a Matched-Sibling Donor after Myeloablative Conditioning Regimen Including 20mg/Kg ATG

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2253-2253
Author(s):  
Francoise Bernaudin ◽  
Azadeh Djavidi ◽  
Cécile Arnaud ◽  
Annie Kamdem ◽  
Isabelle Hau ◽  
...  
Keyword(s):  
Cord Blood ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
Biological Data ◽  
Myeloablative Conditioning ◽  
Post Transplant ◽  
Significant Difference ◽  
T1 And T2

Patients with sickle cell anemia (SCA) have increased susceptibility to infections partially explained by functional splenic and alternative complement pathway defects. Cord blood transplants (CBT) and high doses anti-thymoglobulin (ATG) are suspected to be responsible for viral complications and EBV lymphoma but most of the reports concerned unrelated SCT. The aim of the present study was to compare the immune reconstitution after CBT vs BMT from HLA-identical sibling, in patients prepared with the same myeloablative conditioning regimen (MAC). This retrospective analysis concerns SCA-children all followed in the same CHI-Créteil referral center and transplanted from a HLA-identical sibling with MAC consisting of busulfan, cyclophosphamide and rabbit ATG (Genzyme at 20mg/kg). Pre- and post-transplant clinical and biological data were prospectively recorded in the local database. Lymphocyte subpopulations (CD3+, CD4+, CD8+), IgG, IgA, IgM were recorded each month during the first year post-transplant. Jolly bodies (classified as 0=absent, 1=rare, 2=a few, 3=numerous) and HBs, DTPolio vaccinal serologies were assessed at transplant time (T0), 1 (T1) and 2 years (T2) post-transplant. Revaccination with DTPolio was performed at 1y post-transplant One-hundred-seven SCA-patients (41F,56M) with severe disease were transplanted (1992-2012) with BM (n=83), CB (n=21), CB+BM (=3) at median (range) age: 9.7y (3.4-22.2) for BMT and 6.1y (3.2-12.9) for CBT (p=0.002). Four patients had splenectomy and 5 others partial splenectomy. Rate of rejection was higher after CBT (p=0.002) with 2 non-engraftments and no late rejection whatever the source. TRM was not different despite the occurrence of 3 deaths only after BMT (obliterant bronchiolitis at 1.1year, hemorrhagic stroke at day36, adenoviral encephalitis at month5). Acute GVHD ≥II was observed in 18 patients (16 BMT, 2 CBT) and mild and extensive chronic-GVHD in 5 and 2 patients respectively after BMT and 1 mild after CB+BMT. At 5-year DFS was 95.3% (CI:91.3-99.3%). No significant difference in GVHD and DFS rates was observed according to the source. Neutrophils reached 500/mm3 at mean day32 vs day21 (p<0.001) and platelets reached 50,000/mm3 at day 45 vs 26.5 (p=0.001) after CBT vs BMT. While CD3+ and CD8+ counts never differed between 2 cell sources, CD4+ count was significantly lower until M3 and lymphocyte and CD4+ counts higher after M6 after CBT than BMT (FigAB). After transplant, CMV replications were observed in 38 patients (36 reactivation and 2 primary infection) among the 107 patients but no CMV-disease and no significant difference in the incidence between BMT: 29/83 (34.9%) and CBT: 7/21 (33.3%). EBV replication required anti-CD20 treatment in 5 patients (1 CB, 4 BMT) but no lymphoma occurred. No late infectious complication nor malignant disease was observed in this series. Chimerism outcome (FigCD) was not different between 2 sources after exclusion of the 2 non-engrafted patients: Donor cells % at 1- and 2-year post-T: 92.8% (4.7) vs 87.9% (16.4) and 92.6% (5.4) vs 86.1% (19.1) after CBT vs BMT. Paired analysis comparing results at T0 vs T1 and T2 showed a significant decrease of the mean (SD) Jolly bodies score from 1.38 (0.85) at T0 to 0.50 (0.81) at T1 and 0.28 at T2 (p<0.001). This improvement was not different after BMT vs CBT (FigE). Mean (SD) IgG decreased from 14.2 g/L (4.0) to 12.6 (4.1) at T1 (p=0.003) and 13.1 (3.0) at T2, IgA from 1.89 g/L (1.24) at T0 to 1.33 (0.80) at T1 (p<0.001) and 1.40 (0.64) at T2 whereas IgM were not significantly modified (Fig FG). This decrease of IgG between T0 and T1 was significantly more important after CBT than BMT (p=0.05). Only 2 patients had IgG< 4g/L, one at 9 and 12m post-BMT and another at 3m post-CBT. Mean (SD) anti-HBs (all from vaccinal origin) decreased significantly from 350 UI/L (395) at T0 to 241 (352) at T1 (p<0.001) with 271 (385) at T2 but no difference was observed in the proportion of protected patients (antiHBs≥10UI/L) after CBT vs BMT. No significant difference was found after BMT vs CBT at T0, T1 and T2 in DTPolio123 serologies nor in the proportion of patients protected against DTPolio123 at T0, T1 and T2 (FigH) We confirm the improvement of splenic function after SCT and conclude that contrary to unrelated CBT and SCT using high dose ATG, CBT from HLA-identical sibling do not expose significantly to more frequent viral infections or reactivations and have satisfactory vaccinal response Figure Disclosures Bernaudin: BlueBirdBio: Consultancy; AddMedica: Honoraria, Other: Help for travel; GBT: Membership on an entity's Board of Directors or advisory committees. Socie:Alexion: Consultancy.

Early and Favourable Immune Reconstitution After Unmanipulated Haploidentical Stem Cell Transplantation With High Dose Post-Transplant Cyclophosphamide Regardless Intensity Of Conditioning Regimen

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4620-4620
Author(s):  
Isabel Gonzalez-Gascon y Marin ◽  
Ana María Pérez-Corral ◽  
Jorge Gayoso ◽  
Javier Anguita ◽  
Ana Carolina Franco ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
High Dose ◽  
Post Transplant ◽  
Haploidentical Stem Cell Transplantation

Introduction Favourable immune reconstitution (IR) has been reported after reduced intensity conditioning (RIC) Unmanipulated Haploidentical Stem cell transplantation (Haplo SCT) with high dose post-transplant cyclophosphamide, and it has been suggested as a relevant factor for the good clinical outcomes observed. Due to the encouraging results in our centre the intensity of conditioning regimen has been increased in some patients with high risk of relapse. The aim of this study is to analyze whether the increase in intensity of conditioning influences immune reconstitution after Haplo-SCT. Methods and patients 22 patients (pts) with high risk hematologic malignancies treated in our centre with Haplo-SCT from 2007 to 2013 were included in the analysis. 8 pts received myeloablative(MA) conditioning regimen(fludarabine 30 mg/m2 IV (day -6 to -3) and busulfan 3.2 mg/kg IV (day -6 to -3) or fludarabine 30 mg/m2 IV (day -6 to -2), cyclophosphamide 14.5 mg/kg (day -6 to -5), and busulfan 3.2 mg/kg IV (day -4 to -2)). 14 pts received RIC conditioning regimen (fludarabine 30 mg/m2 (day -6 to -2), cyclophosphamide 14.5 mg/kg (day -6 and -5), and busulfan 3.2mg/kg IV (day -3 or day -4 to -3)). GVHD prophylaxis was high dose cyclophosphamide on days +3 and +4, cyclosporine A and mycophenolate mofetil for all patients. Median age was 43 years (26-65) and underlying diseases included: AML (8); ALL (1); MDS (2); MM (2); Hodgkin´s disease (7); mantle cell lymphoma (1); accelerated myelofibrosis (1). Median follow-up was 16 m (5-53). 13 pts were alive and disease-free at last follow-up and 4 pts died (3 relapse, 1 progressive multifocal leukoencephalopaty). We evaluated lymphocyte subsets (absolute numbers of CD3, CD4, CD8, CD19, NK, NKbright, and CD19) by flow cytometry (FC500 Beckman Coulter® cytometer) at 1, 3, 6, 9 and 12 months (m) post Haplo-SCT in the two groups (MA and RIC conditioning regimen). Immunoglobin serum levels were recorded at the same time points. For comparison Mann–Whitney U-test was used. Results In the 22 pts, NK cells were the first lymphocyte subset to recover with a median of 84/μl (5-480) and 145/μl (12-562) by m1 and m3 respectively. A high proportion of NKbright cells was observed at m1 post-transplant. This NKbright population decreased from a median of 83% (15-95) at m1 to 32% (9-95%) at m3, and 30% (9-57%) at m6. CD3+ T-lymphocytes (TL) reached normal levels at m3 after haplo-SCT (median 1109/μl (40-3187), and remained at normal range throughout the study period. CD4+ reached levels > 200/μl at m3 with a median of 247/μl (1-570), and also remained above this threshold during the follow up. Reconstitution of CD19+ B lymphocytes was adequate, with a median of 2/μl (0-76); 91/μl (0-556); 139/μl (3-600); 238 (105-575) and 236/μl (12-1098) on m1, 3, 6, 9 and 12 respectively. No difference was observed between RIC and MA conditioning for NK, NKbright; CD3+, CD4+, CD8+ T-lymphocyte and CD19+ B-lymphocyte count recovery. IgM was the first immunoglobulin to recover, reaching normal levels by m3 (61 mg/dL (10-264)), followed by IgG (normal levels at m12 (692 mg/dL (242-1530)). IgA reconstitution was delayed and did not reach normal levels by m12, as described before. No difference was found between RIC and MA conditioning for immunoglobulin recovery. Table 1 shows IR after haplo-SCT. Conclusions Rapid and favourable immunologic recovery was observed after haplo-SCT as reported before. Intensity of conditioning did not have any significant impact on the kinetics of immune recovery. Acknowledgments This work has been partially supported by Project “Evaluación de la reconstitución inmune después del trasplante haploidéntico de progenitores hemopoyéticos sin depleción T” from Fundación Mutua Madrileña. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CXCR6-CXCL16 Axis Promotes Breast Cancer by Inducing Oncogenic Signaling

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3568
Author(s):  
Hina Mir ◽  
Neeraj Kapur ◽  
Dominique N. Gales ◽  
Praveen K. Sharma ◽  
Gabriela Oprea-Ilies ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Actin Polymerization ◽  
Biological Significance ◽  
Stage Ii ◽  
Stage Iii ◽  
Soluble Form ◽  
Migration And Invasion ◽  
Antibody Microarray ◽  
Terminal Fragment ◽  
Significant Difference

Precise mechanisms underlying breast cancer (BrCa) metastasis are undefined, which becomes a challenge for effective treatments. Chemokine signaling instigates the trafficking of cancer cells in addition to leukocytes. This study aimed to ascertain the clinical and biological significance of the CXCR6/CXCL16 signaling axis in the pathobiology of BrCa. Our data show a higher expression of CXCR6 in BrCa cell lines and tissues. Stage-III BrCa tissues express significantly higher CXCR6 compared to stage-II tissues. The ligand, CXCL16, could remain tethered to the cell surface, and, after proteolytic shedding of the ectodomain, the N-terminal fragment is released, converting it to its oncogenic, soluble form. Like CXCR6, N-terminal CXCL16 and ADAM-10 were significantly higher in stage-III than stage-II, but no significant difference was observed in the C-terminal fragment of CXCL16. Further, stimulation of the CXCR6/CXCL16 axis activated Src, FAK, ERK1/2, and PI3K signaling pathways, as per antibody microarray analysis, which also underlie CXCL16-induced F-actin polymerization. The CXCR6/CXCL16 axis induces cytoskeleton rearrangement facilitating migration and invasion and supports BrCa cell survival by activating the PI3K/Akt pathway. This study highlights the significance of the CXCR6/CXCL16 axis and ADAM10 as potential therapeutic targets for advanced-stage BrCa.

CD4/CD8 ratio improvement in HIV-1-infected patients receiving dual antiretroviral treatment

2019 ◽  
Vol 30 (7) ◽  
pp. 656-662 ◽  
Author(s):  
Marta Monsalvo ◽  
Alejandro Vallejo ◽  
María Fontecha ◽  
María J Vivancos ◽  
Pilar Vizcarra ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Ratio Increase ◽  
Related Factors ◽  
Cd4 Cell Count ◽  
Lower Baseline ◽  
Baseline Values ◽  
A Prospective Study ◽  
Aids Diagnosis ◽  
Cd4 Cell ◽  
Hiv 1

The CD4/CD8 ratio is an indirect marker of immune activation, immune senescence, and inflammation in HIV infection. We performed a prospective study of the CD4/CD8 ratio evolution in 245 virally-suppressed (median, 55 months) HIV-infected patients (29% females) who had switched to four dual antiretroviral regimens. At baseline, the median CD4/CD8 ratio was 0.71 (interquartile range, IQR, 0.46–0.97), associated with duration of HIV infection, nadir CD4+ cell count, and AIDS diagnosis. It was lower in the case of hepatitis C virus coinfection and cardiovascular disease (p = 0.09), but the ratio was higher in patients with chronic kidney disease, proteinuria, or osteoporosis. At 48 weeks, the median CD4/CD8 ratio increased by 3% (+0.02; IQR, –0.07, +0.09; p = 0.07); greater improvement was observed in patients with lower baseline ratios and previous AIDS diagnosis. The slope of increase was slower in patients with the highest baseline values. Also, there were no differences in the CD4/CD8 ratio increase according to type of dual regimen, after adjusting for baseline and HIV-related values. In conclusion, CD4/CD8 ratio increase is observed during suppressive dual regimens, and its extent is related to baseline values and previous HIV-related factors. Longer duration on antiretroviral therapy and drug toxicity could affect the evolution of this marker in the presence of comorbidities.

Sign in / Sign up

Export Citation Format

Share Document