scholarly journals The importance of CD34 positive cell quantification for Hematopoietic stem cell mobilization

JBMTCT ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. p94
Author(s):  
Patricia Elkiki dos Santos
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Mononuclear Cells ◽  
Leukocyte Count ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Significant Difference

Abstract Objective: The success of autologus hematopoietic stem cell transplantation relies on CD34+ cells' availability in peripheral blood (PB),  which is affected by several factors as age, sex, type of the disease, treatments, and others. In that regard, this prospective study aimed to evaluate the influence of these factors, correlating them with the pre-apheresis CD34+ cell count. Method: Before autologous hematopoietic stem cell transplantation, CD34+ cells were quantified in the pre-apheresis PB and the final product. Then, after the determination of minimum CD34+ value, clinical and laboratory parameters were compared between patients with higher and lower CD34+ cells count. Results: Out of the 34 patients, 29 presented more than 20,000 leukocytes/μl. Patients who failed in the mobilization presented <20,000 leukocytes/μl. There was a significant difference between the groups with different pre-apheresis CD34+ cells status regarding age (p=0.025), leukocyte count (p<0.001) and mononuclear cells (p=0.001) in PB. In addition, the pre-apheresis CD34+ ≥14 cells/μl group was related to a better yield of these cells in the final product and with the requirement of a single collection to obtain the minimum yield, of 2x106 CD34+/kg. Conclusion: This study demonstrates age and leukocyte count relate to CD34+ count in PB, and that CD34+ cells yield in the collection, can be predicted by  CD34+ cells frequency in PB.

The Importance of the Number of Transplanted Cells with Dipeptidyl Peptidase-4 Expression on the Hematopoietic Recovery and Lymphocyte Reconstitution in Patients with Multiple Myeloma after Autologous Hematopoietic Stem-Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5415-5415
Author(s):  
Anna Kopinska ◽  
Malgorzata Krawczyk-Kulis ◽  
Joanna Dziaczkowska-Suszek ◽  
Katarzyna Bieszczad ◽  
Krystyna Jagoda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Dipeptidyl Peptidase 4 ◽  
Hematopoietic Recovery ◽  
Cd34 Cells

Abstract Introduction Autologous hematopoietic stem cell transplantation (AHSCT) remains the treatment of choice in multiple myeloma (MM) patients (pts). In earlier research it has been suggested that the expression of dipeptidyl peptidase-4 (DPP4, CD26) influences both the homing and lymphocyte reconstitution after AHSCT in pts with lymphoproliferative neoplasms. The aim of the study is to investigate the effect of transplanted CD26 positive cells of the hematopoietic recovery and lymphocyte reconstitution in MM pts after AHSCT. Patients and methods Forty eight pts with MM with median age 56 (range 21-76) were undergoing AHSCT in our center in years 2011-2013. Conditioning regimen was Melphalan 200. Number of all CD26+ cells, CD26+ lymphocytes, CD26+ monocytes and CD26+ and CD34+ cells were measured in harvested material. Number of lymphocyte's subpopulations (all lymphocytes CD3+, helpers CD3+CD4+, suppressors CD3+CD8+, natural killer (NK) CD3-CD16+CD56+, cytotoxic NK CD3+CD16+CD56+, lymphocytes B CD3-CD19+) were measured in peripheral blood during regeneration period after AHSCT. In both flow cytometry was used. The hematopoietic regeneration was measured as following: the day of white blood cells' regeneration when WBC count reached >1,0x109/L, the day of granulocytes' regeneration when ANC >0,5x109/L and the day of platelets' regeneration when PLT >20x109/L. Results All pts successfully engrafted. The results of AHSCT are shown in table nr 1. Table 1. The number of transplanted cells and regeneration during the procedure AHSCT in pts with MM. Parameter Median Range Mean Standard deviation Number of transplanted WBCx108/kg b.w. 4,26 0,73-18,8 5,43 4,36 Number of transplanted CD34+cells x106/kg b.w. 3,36 2,2-8,2 3,52 1,28 Number of transplanted CD26+ lymphocytes [109/L] 46,5 9-148 53,6 30,8 Number of transplanted CD26+ monocytes [109/L] 3,65 0-82 8,03 13,05 Number of all transplanted CD26+ cells [109/L] 50,42 9,6-213 62,5 23,2 Regeneration WBC >1x109/L (day) 13 10-20 13 2,64 ANC >0.5x109/L (day) 13 9-20 13,3 2,16 PLT >20x109/L (day) 14 11-20 14,1 2,18 As regards regeneration of hematopoietic cells after AHSCT it was shown that a higher number of transplanted CD26+ monocytes improves the reconstitution of suppressor (p=0,019) and NK lymphocytes (p=0,0237). A higher number of all transplanted CD26+ lymphocytes has a positive impact of the reconstitution of suppressor lymphocytes (p=0,0054), whereas a higher number of all transplanted the CD26+ cells improves the regeneration of cytotoxic NK (p=0,0126) and helper lymphocytes (p=0,0261). There were no confirmed adverse effects of the number of CD26+ cells on the hematopoietic regeneration0 and lymphocytes B reconstitution after AHSCT. Discussion Our research shows that the number of transplanted CD26-positive cells may improve immune reconstitution after AHSCT in patients with multiple myeloma, which was not clearly demonstrated before. As is well known faster lymphocyte reconstitution after AHSCT is associated with improved patient survival. Therefore, the greater the number of transplanted autologous CD26-positive cells may be associated with improved survival, which, however, needs further investigation. Disclosures No relevant conflicts of interest to declare.

Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)–rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2644-2650 ◽  
Author(s):  
Georg Mann ◽  
Andishe Attarbaschi ◽  
Martin Schrappe ◽  
Paola De Lorenzo ◽  
Christina Peters ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Lymphoblastic Leukemia ◽  
Mixed Lineage Leukemia ◽  
Hematopoietic Stem ◽  
Significant Difference

AbstractTo define a role for hematopoietic stem cell transplantation (HSCT) in infants with acute lymphoblastic leukemia and rearrangements of the mixed-lineage-leukemia gene (MLL+), we compared the outcome of MLL+ patients from trial Interfant-99 who either received chemotherapy only or HSCT. Of 376 patients with a known MLL status in the trial, 297 (79%) were MLL+. Among the 277 of 297 MLL+ patients (93%) in first remission (CR), there appeared to be a significant difference in disease-free survival (adjusted by waiting time to HSCT) between the 37 (13%) who received HSCT and the 240 (87%) who received chemotherapy only (P = .03). However, the advantage was restricted to a subgroup with 2 additional unfavorable prognostic features: age less than 6 months and either poor response to steroids at day 8 or leukocytes more than or equal to 300 g/L. Ninety-seven of 297 MLL+ patients (33%) had such high-risk criteria, with 87 achieving CR. In this group, HSCT was associated with a 64% reduction in the risk of failure resulting from relapse or death in CR (hazard ratio = 0.36, 95% confidence interval, 0.15-0.86). In the remaining patients, there was no advantage for HSCT over chemotherapy only. In summary, HSCT seems to be a valuable option for a subgroup of infant MLL+ acute lymphoblastic leukemia carrying further poor prognostic factors. The trial was registered at www.clinicaltrials.gov as #NCT00015873 and at www.controlled-trials.com as #ISRCTN24251487.

Dendritic Cells Reconstitution after Different Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5211-5211
Author(s):  
De Pei Wu ◽  
Junjie Cao ◽  
Caixia Li ◽  
Xiaojin Wu
Keyword(s):  
Dendritic Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Hla Dr ◽  
Significant Difference ◽  
Kinetics Of

Abstract Objective: To compare the dendritic cells reconstitution after different allogeneic hematopoietic stem cell transplantation in early time Methods: From June 2004 to March 2005, Twenty-eight patients undergoing allo-HSCT were enrolled in this study. There were 16 patients who undergone normal HSCT, 8 patients who undergone Haploidentical HSCT and 4 patients who undergone Nonmyeloablative HSCT. Three-colour flow cytometry was applied to study the alteration of the percentage and number in circulating peripheral blood dendritic cells subsets on day 14,day 30,day 60 after transplantation among three distinct type HSCT. Results: The dendritic cells subsets number of myeloablative HSCT patients were very low. No difference was observed in the kinetics of DC1 (Lin−HLA-DR+CD11c+)and DC2 (Lin−HLA-DR+CD123+) reconstitution between the normal HSCT group and Haploidentical HSCT group patients(p&lt;0.05). There was significant difference between myeloablative HSCT group and normal healthy individuals(p&lt;0.01). There was significantly different between the non-myeloablative HSCT group and the myeloablative HSCT group in the kinetics of DC1 and DC2 reconstitution(p&lt;0.05). Conclusion: The early reconstitution of dendritic cells in Nonmyeloablative HSCT patients is earlier than the patients who undergone myeloablative HSCT. The early reconstitution of dendritic cells in normal HSCT and Haploidentical HSCT patients were later than others.

Minoriting Cvtomegalovirus after Hematopoietic Stem Cell Transplantation for Seven Years-a Single Center Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4376-4376
Author(s):  
Xiaojin Wu ◽  
Wu Depei ◽  
Aining Sun ◽  
Xiaowen Tang ◽  
Zhengzheng Fu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Antiviral Therapy ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract Objective: To investigate the incidence, risk factor and management of CMV reactivation in patients revived hematopoietic stem cell transplantation(HSCT). Methods: 374 patients including 275 consecutive allogeneic and 99 autologous patients after bone marrow/stem cell transplantation from May 2001 to December 2007 were studied at our institution with nest-PCR and pp65 antigen assay. Anticoagulant blood samples were obtained from the recipients once weekly after days 14. After three months the CMV monitoring was performed every one month or every three months. If the patients catch CMV again after three year, the CMV monitoring was performed again. Results: The incidence of CMV positive in autologous patients was 3.03% and was 54.91% in allogeneic patients with a median onset of 48 days post transplants during 1 to 81 months. The difference between them is significant; The infection rate in the nonmyeloablative allogeneic peripheral stem cell transplantation (NST) group was 61.76%, in the group of HLA—identical sibling donor HSCT(sib-HSCT) was 47.10%, in haploidentical hematopoietic stem cell transplantation (Hi-HSCT) group was 75.00% and in the group of unrelated bone marrow transplantation (UR-BMT) was 57.45%. The infection rate of CMV in the Hi-HSCT group was higher than that in the group of sib-HSCT with significant difference (P&lt;0.05); The incidence rate of CMV infection in patients with regimen including ATG was higher than that without ATG ((65%&47.1%, P&lt;0.05); The incidence rate of CMV infection in patients with III–IV grade aGVHD and patients without III–IV aGVHD had not significant difference (P&gt;0.05). There was not significant difference in the occurance of aGVHD between the patients with and without CMV infection (P&gt;0.05).5.87.8% patients are effective on antiviral therapy, incidence of CMV disease is very low, 0.65% patients catch CMV more than once. Conclusion FCMV infection is common in our study, Minoriting CMV for long time is necessary, which benefit to antiviral therapy and judging of prognosis.

Double Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation: French Society of Bone Marrow Graft Transplantation and Cellular Therapy Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4293-4293
Author(s):  
Jacques-Olivier Bay ◽  
Aurelie Cabrespine-Faugeras ◽  
Reza Tabrizi ◽  
Pierre Bordigoni ◽  
Karin Bilger ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Median Time ◽  
Biological Data ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Reduced Intensity

Abstract Purpose: Objective was to assess indication, feasibility and efficacy of double allograft with reduced intensity conditioning. Patients and Methods: All double allogeneic hematopoietic stem cell transplantation (AHSCT) after reduced intensity regimen reported to Promise database were retrospectively studied. Because of the initial lack of clinical and biological data in the Registry, all centers were contacted to improve the database. Results: 66 double mini-allografts were realized in 25 french transplant centers. At this time, 35 mini-allografts presented complete informations corresponding to 14 transplant centers. Diagnosis was LAM (n=15), aplasic anemia (n=5), MDS and/or MPS (n=5), LAL (n=2), Myeloma (n=2), ovarian cancer (n=1), LNH (n=2), LLC (n=1), LMC (n=1) and Hodgkin lymphoma (n=1). Median age at first transplantation was 49.3 years [12.75–64.9] with a median time from diagnosis to first transplant of 22.9 months [3.6–163.7]. Disease status before transplant was progression (n=5), partial response (n=3), complete response (n=18), induction failure (n=2) and chronic phase (n=2). The 5 aplasic anemias were not evaluable for this status. Most patients received fludarabine (n=31), SAL (n=22), busulfan (n=15) based regimen. Graft source was PBSC in 74% of grafts. Median age of donor was 42 years [4–68]. HLA relation of donor with patient was identical sibling (n=22), match unrelated (n=10) or mismatch unrelated (n=3). Second allograft indication was relapse (n=22), lost of graft (n=7), no engraftment (n=5) or residual disease (n=1). Eihgty percents of patients underwent a different conditioning. It was similar for only 7 patients (same n=1, increase SAL dose n=1, SAL addition n=2, dose reduction n=1). Median time between the two allografts was of 7.6 month [1.1–61.0]. Source of stem cells and donor were changed in 13.6% and 37% of allograft respectively. The median time to reach an absolute neutrophil count of 0.5 × 109/l and platelet count of 50 × 109/l was shorter after second allograft (21.4 days [12.4–759.5] versus 16.8 days [6.2–105.4] and 16.3 days [9.3– 71.3] versus 14.26 [3.1–83.7]) with no significant difference. Overall incidence of acute GvH was similar after the two allografts (34% versus 43%). However, acute GvH grade III–IV proportion seems to be higher after second allograft (8% versus 40%). Similarly, proportion of chronic GvH was 23% versus 27% with an increase of extensive GvH after second allograft (50% versus 66%). Response was improved by second allograft in five patients (15%) and allowed to engraftment in 3 patients (7%). To date, 8 patients are still alive. 14 patients died from progression and 11 of TRM (3 multiple organ failure, 5 respiratory failure, 2 fungal infection and 1 rejection) giving a TRM proportion of 31%. With a median follow-up of 57.1 months [21.9–128.8], the median overall survival (OS) was of 24 months [2–71]. Delay greater than 7.7 months and same source of stem cell between two mini-allografts improved OS (50 months versus 9 months, p = 0.0085 and 28 months versus 14 months, p=0.11). Conclusions: Our preliminary results suggests response improvement after double AHSCT with reduced conditioning. However, TRM proportion was high.

scholarly journals Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5394-5402 ◽  
Author(s):  
Cristina Cunha ◽  
Mauro Di Ianni ◽  
Silvia Bozza ◽  
Gloria Giovannini ◽  
Silvia Zagarella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Invasive Aspergillosis ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Mononuclear Cells ◽  
Stop Codon ◽  
Hematopoietic Stem ◽  
Antifungal Immunity

Abstract The C-type lectin receptor Dectin-1 plays a pivotal role in antifungal immunity. In this study, the recently characterized human DECTIN1 Y238X early stop codon polymorphism leading to diminished Dectin-1 receptor activity was studied in relation to invasive aspergillosis susceptibility and severity in patients receiving hematopoietic stem cell transplantation. We found that the presence of the DECTIN1 Y238X polymorphism in either donors or recipients of hematopoietic stem cell transplantation increased susceptibility to aspergillosis, with the risk being highest when the polymorphism was present simultaneously in both donors and recipients (adjusted hazard ratio = 3.9; P = .005). Functionally, the Y238X polymorphism impaired the production of interferon-γ and interleukin-10 (IL-10), in addition to IL-1β, IL-6, and IL-17A, by human peripheral mononuclear cells and Dectin-1 on human epithelial cells contributed to fungal recognition. Mechanistically, studies on preclinical models of infection in intact or bone marrow-transplanted Dectin-1 knockout mice revealed that protection from infection requires a distinct, yet complementary, role of both donor and recipient Dectin-1. This study discloses Dectin-1 deficiency as a novel susceptibility factor for aspergillosis in high-risk patients and identifies a previously unsuspected role for Dectin-1 in antifungal immunity that is the ability to control both resistance and tolerance to the fungus contingent on hematopoietic/nonhematopoietic compartmentalization.

scholarly journals Pharmacokinetics of mycophenolic acid after haplo-hematopoietic stem cell transplantation in Japanese recipients

2020 ◽  
pp. 107815522098081
Author(s):  
Kazuki Uchiyama ◽  
Yoshitaka Saito ◽  
Yoh Takekuma ◽  
Junichi Sugita ◽  
Takanori Teshima ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Mycophenolic Acid ◽  
Enterohepatic Circulation ◽  
Pharmacokinetic Parameters ◽  
Hematopoietic Stem ◽  
Significant Difference

Purpose Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) prodrug, is used to prevent graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). Although previous studies have reported that enterohepatic circulation (EHC) of MPA, which is usually observed in MMF-treated patients, does not occur in HSCT patients, it is unclear what happens in haploidentical–HSCT (haplo-HSCT) patients, who are using post-transplant cyclophosphamide. This study was conducted to investigate MPA pharmacokinetics in haplo-HSCT patients. Methods Seventeen haplo-HSCT patients, who received MMF for GVHD prophylaxis, were enrolled in this study. We collected blood samples on days 14 and 28, and plasma MPA concentrations were measured by high-performance liquid chromatography; pharmacokinetic parameters such as area under the curve (AUC), mean residence time (MRT), and apparent oral clearance (CL/F) were measured with moment analysis. We also evaluated EHC as AUC6-12h/AUC0-12h. Results There was no significant difference in MPA pharmacokinetic parameters between days 14 and 28. There was also no difference between the pharmacokinetic parameter changes and diarrhea. Additionally, varying plasma MPA concentrations suggested that MPA EHC did not occur. Conclusion In this study, we revealed the pharmacokinetics of MMF in Japanese haplo-HSCT recipients. Additionally, our study demonstrated that MPA EHC might not occur in Japanese haplo-HSCT recipients.

CD34+ Hematopoietic Progenitor Cells Express CD 184 Antigen and to a Minor Extend MMP9.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4032-4032
Author(s):  
Jens Abendroth ◽  
Hans J. Schmoll ◽  
Hans-Heinrich Wolf
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Immune Defense ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem ◽  
Mmp9 Expression ◽  
Cd34 Cells

Abstract For clinical purposes the CD34 surface antigen characterises hematopoietic progenitor or stem cells (HSC) and will be measured routinely for peripheral hematopoietic stem cell transplantation (PBSCT). Concerning homing mechanisms of HSC not only the number of CD34+ cells could be important. However, there are several other characteristic surface antigens indicating proliferation. For example, the cell surface receptor CD184 has been found on CD34+ HSC and seems to be necessary for stem cell development and migration. CD184 knock-out mice are known to present insufficient hemato- and lymphopoiesis. MMP9, a gelatinase cleaving collagen typ IV, expressed on HSC, is necessary for migration and probably also for HSC engraftment. In leukapheresis products used for PBSCT we were interested in CD184 and MMP9 protease expression on CD34+ cells and their impact on homing. Methods: 84 leukapheresis products for autologous stem cell transplantation were analysed in 65 patients. The patients suffered from oncologic (n= 45) and haematological (n=20) malignancies. There was no bone marrow infiltration found before starting leukapheresis. Expression of CD184 and MMP9 on CD34+ cells were analysed by flow cytometry. Additionally, the number of CD45+ cells was measured (BD Biosciences). Statistical analysis was run by SPSS using students t-test and Mann-Whitney-U test. Results: 44,7% (+/− 3,1%) of CD34+ cells presented the CD184+ antigen, but MMP9+ expression was found only in 5% (+/− 1,4%) of CD34+ HSC, respectively. Regarding the patients age, sex or underlying diseases no significant differences were seen. Discussion: High expression rate of CD184 antigen and MMP9 on CD34+ HSC could be favorable for engraftment and success of hematopoietic stem cell transplantation. Surprisingly, in our study on leukapheresis products less than half of CD34+cells were found to express CD184+ antigen, and only 5% presented MMP9 expression. As time to engraftment after PBSCT of the patients did not differ from mean values either antigen expression could develop on a further step of hematopoietic reconstitution or the patients presented an "alternative pathway" establishing hematopoiesis and immune defense mechanisms. Further studies on proliferation and differentiation mechanisms of HSC are requested.

Successful Allogeneic Hematopoietic Stem Cell Transplantation for Severe Inflammatory Bowel Disease – IL10 Receptor Deficiency May Serve as a Novel Therapeutic Paradigm

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2379-2379 ◽  
Author(s):  
Rita Beier ◽  
Daniel Kotlarz ◽  
Kaan Boztug ◽  
Erik Glocker ◽  
Eva Doreen Pfister ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Mononuclear Cells ◽  
Mixed Chimerism ◽  
Hematopoietic Stem ◽  
Inflammatory Bowel

Abstract Abstract 2379 Inflammatory bowel diseases (IBDs) comprise a heterogeneous group of disorders, classically defined as Crohn's disease, ulcerative colitis, and indeterminate colitis. The molecular pathophysiology of enterocolitis is still largely unknown. Recently, we identified monogenic mutations in the IL10 receptor genes, providing novel insights into the role of IL10-mediated immune homeostasis in the human gut. Here, we report a series of 8 patients with mutations in the IL10RA or IL10RB gene. All patients presented within the first three months of life with severe enterocolitis and rectal fistulations. Patients were unresponsive to immunosuppressive and immunomodulatory therapies. Deleterious mutations in IL10 receptor genes abrogated IL10-induced signaling, as demonstrated by deficient STAT3 phosphorylation at the tyrosine 705 residue upon IL10 stimulation. As a consequence of defective STAT3 signal transduction in response to IL10 stimulation, IL10R-deficient mononuclear cells showed increased secretion of TNFα and various other proinflammatory cytokines unresponsive to IL10-dependent negative feedback regulation (TGFβ1, IL1α, IL1β, IL2, IL6, IL6sR, RANTES, MCP1, MIP1α, and MIP1β). In view of the critical immunomodulatory role of IL10, we designed a protocol for allogeneic hematopoietic stem cell transplantation for patients with IL10R-mutations. The conditioning regimen includes treosulfan, fludarabin, thiotepa, and campath-1A. A strict gut decontamination regime was chosen to reduce intestinal bacterial load. Ciclosporin A, mycophenolatemofetil, and campath-1A was used for graft versus host disease prophylaxis. 4 patients (age at HSCT 0.9–13.8yrs, 3 male, 1 female) were transplanted from a HLA-identical matched sibling (n=2) or a matched unrelated donor (MUD, HLA match 9/10) (n=2). All patients engrafted(neutrophil engraftment 10–26 days). In 3/4 patients displayed full chimerism after the first HSCT. One patient developed mixed chimerism on day 69 after HSCT and consecutively lost his graft. He was successfully re-transplanted from a different 9/10 MUD successfully achieving full donor chimerism. Acute GvHD II° and III° (skin) occurred in one patient each and was treated successfully, no chronic GvHD was observed. Regimen related toxicity was low and included mucositis I-II° and skin toxicity I-II°. Viral infections were diagnosed and successfully treated in 3/4 children (1 CMV, 1 adenovirus, 1 rotavirus). These patients responded well to the antiviral treatment or reduction of immunsuppression (follow up after HSCT 6 months-2 yrs). Intestinal inflammation resolved as proven by clinical examination, colonoscopy and histological analysis. All children improved their growth rate following the bone marrow transplantation. Post transplant samples taken after transplant showed a restored response to IL10 in mononuclear cells. These data suggest that allogeneic HSCT may represent a novel, effective, and safe therapeutic approach to treat defined subgroups of IBD patients. Disclosures: No relevant conflicts of interest to declare.

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