scholarly journals HLA donor-specific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 645-650 ◽  
Author(s):  
Douglas E. Gladstone ◽  
Maria P. Bettinotti
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Solid Phase ◽  
Hla Antigens ◽  
Relative Strength ◽  
Hematopoietic Stem ◽  
Strength Assessment ◽  
Specific Antibodies ◽  
Challenges And Opportunities ◽  
Donor Specific Antibodies

Abstract Allogenic hematopoietic stem cell recipients may have preformed antibodies directed against foreign HLA antigens. The use of partially HLA-mismatched allogeneic hematopoietic stem cell donors allows for the possibility of the presence of circulating HLA donor-specific antibodies (DSAs) in the recipient. The presence of DSAs at the time of stem cell infusion increases the risk of primary graft failure. More recently developed technology using solid phase immunoassays (SPIs) with fluorochrome-conjugated beads has greatly improved the ability to detect and classify DSAs. When used in combination with the classic lymphocytotoxic complement-dependent and flow cytometric crossmatch tests, SPIs help provide DSA strength assessment. Parous females frequently harbor DSAs. DSAs tend to be of higher intensity when directed against haploidentical first-degree relatives. DSA assessment requires frequent monitoring as their relative strength can change over time. Although the criteria that constitutes a prohibitive DSA is unknown, desensitization techniques can result in engraftment rates as experienced in fully HLA-matched allogeneic blood or marrow transplantation recipients.

Desensitization for Mismatched Hematopoietic Stem Cell Transplantation (HSCT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1955-1955 ◽  
Author(s):  
Douglas Edward Gladstone ◽  
Andrea Zachary ◽  
Ephraim J. Fuchs ◽  
Leo Luznik ◽  
Yvette L. Kasamon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hla Antigens ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Specific Antibodies ◽  
Post Transplant

Abstract Abstract 1955 Introduction: Sensitization to donor HLA antigens is associated with an increased risk of engraftment failure in HLA mismatched hematopoietic stem cell transplantation (HSCT). However, the use of partially mismatched donors is increasing since, at best, only 30% of patients have an HLA identical sibling donor available for transplantation, and many are unable to find a matched unrelated donor in a timely fashion. A non-myeloablative, T cell replete regimen for HSCT that utilizes post-transplant high dose, cyclophosphamide for graft-versus-host-disease (GVHD) prophylaxis was pioneered at Johns Hopkins and has permitted transplantation of over 200 patients with HLA-haploidentical related donors. The use of HLA haplo-identical donors greatly increases the numbers of potential donors for most HSCT candidates. Review of the evaluations of 148 consecutive candidates for haplotransplantation revealed that 95% had at least one haplo-identical donor with an average of 2.7 donors/patient. However donor specific HLA antibody (DSHA) was observed in 10.8% of patients. We report here, successful desensitization of (DHSA) to levels safe for HSCT in six broadly sensitized patients who had poor-risk hematologic malignancies and for whom there were no other donors for whom HLA specific antibodies were not an issue. Methods: The desensitization protocol was modified from that developed for renal transplant patients at the Johns Hopkins University Comprehensive Transplant Center and included alternate day, single volume plasmapheresis (PP) with low dose, 100mg/kg, anti-CMV hyper immune immunoglobulin (IVIg) under immunosuppression with tacrolimus and mycophenolate mofetil. Varying numbers of PP/IVIg treatments were scheduled prior to the non-myeloablative conditioning regimen according to each patient's DHSA level. PP/IVIg was stopped during conditioning. All but one patient received one additional PP/IVIg at transplant day −1. HLA antibodies were assessed by solid phase immunoassays using panels of pooled HLA antigens, HLA phenotypes, and single HLA antigens in microbead suspension array immunoassays (GenProbe Lifecodes Inc., San Diego, CA; One Lambda, Inc., Canoga Park, CA) Results and conclusions: All six patients prior to desensitization had DHSA at levels sufficient to yield positive flow cytometric crossmatch (FCXM) tests defined as 12K molecules of equivalent soluble fluorochromes (MESFs). The donor specific antibodies were reduced to levels well below a positive FXCM in all six patients by the end of the PP/IVIG treatments and before transplantation through an average of 4.2 PP/IVIg treatments. The average reduction in the donor specific antibody strength was 71.5% (range: 52–91%). In three patients, the DHSA levels were reduced to negative by time of transplant. A fourth patient was transplanted with a DHSA level just below that consistent with a positive FCXM, but by three months post-transplant had completely eliminated the DHSA. Two patients received one additional post-transplant PP/IVIg, resulting in stable DSA levels well below a +FCXM. Sufficient post-transplant follow-up of more than four months was available for four patients of which 3 received grafts from haploidentical donors and 1 from an HLA-mismatched unrelated donor. All four of these fully engrafted with no acute GVHD episodes. These results demonstrate that desensitization can extend the opportunity for HSCT to sensitized patients with no other donor options. Disclosures: Luznik: Otsuka Pharmaceuticals: Research Funding.

scholarly journals Synthesis and Two-Dimensional 1Η and 13C NMR Investigations of an Inhibitor of Hematopoietic Stem Cell Proliferation Ac–Ser–Asp–Lys–Pro–OH

1992 ◽  
Vol 47 (9) ◽  
pp. 1324-1332 ◽  
Author(s):  
Jens Freund ◽  
Afroditi Kapurniotu ◽  
Tadeusz A. Holak ◽  
Maryse Lenfant ◽  
Wolfgang Voelter
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Solid Phase ◽  
Water Solution ◽  
Random Coil ◽  
Hematopoietic Stem ◽  
Stem Cell Proliferation ◽  
Equilibrium Ratio

The solid phase synthesis of the inhibitor of hematopoietic stem cell proliferation, Ac–Ser–Asp–Lys–Pro–OH, and its derivative Ac–Ala–Asp–Lys–Pro–OH is described. 1H and 13C NMR investigations demonstrate that both peptides show no prefered conformation in water solution. Both peptides exist in a Pro-cis-trans equilibrium ratio of 9 (trans) : 1 (cis). Thymosin β4 is believed to be the precursor molecule of the tetrapeptide Ac–SDKP. The attachement of the random coil tetrapeptide to a rigid helical fragment could facilitate its in vivo enzymatic cleavage.

Prevalence and Significance of Pre-Formed Anti-HLA Antibodies in Hematopoietic Stem Cell Transplant Recipients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1174-1174
Author(s):  
Darshan Gautam Gandhi ◽  
Jennifer Holter ◽  
Mohamad Khawandanah ◽  
Robert B. Epstein ◽  
Julie Stoner ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Graft Failure ◽  
Hla Antigens ◽  
Class Ii ◽  
Class I ◽  
Hla Antibodies ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Antibody Levels

Abstract Abstract 1174 Poster Board I-196 Introduction: The presence of sensitization to HLA antigens has been an important consideration in solid organ transplantation. It is considered a standard process to check for donor-specific allogeneic (allo) antibodies (DSA) and monitor formation of such antibodies post-transplant which could predict early and late graft failure. Most of the current data regarding the importance of anti-HLA (human leukocyte antigen) antibodies is available from renal transplant where presence of HLA antibodies is clearly associated with an increased risk of early graft loss up to the magnitude of 21%. It is routine to perform desensitization to alleviate these antibodies in an effort to enhance their chances of engraftment. The role of and approach to prior sensitization in the hematopoietic stem cell transplantation (HSC) setting is far less clear. This is of unique importance as a wider range of donor cell sources and transplant applications are utilized to treat hematologic diseases. Many of our patients have had multiple transfusions in the past, been pregnant or have had prior HLA mismatched allograft, all of which predispose to development of anti-HLA antibodies. Here we analyze the prevalence of Class I and Class II antibodies as a primary goal and also see if they correlate with graft survival. Methods: 52 patients were followed between July 2008 and July 2009 with hematologic malignancies including leukemia's, lymphoma's, multiple myeloma and others. 37/52 underwent transplantation of which 14 were unrelated donor (URD), 5 cord blood (CB) and 8 sibling (sib) transplants. Donors with corresponding HLA were excluded. Post-transplantation with day 100 antibody testing was performed in eligible patients. Antibody determination was done by testing the patients' sera with a panel of fluorescent beads coated with single HLA antigens using a solid-phase Luminex™ platform. Cut-point of 1500 [mean fluorescence intensity (MFI) ≥ 1500 defined as positive] was used for performing statistical analyses. The prevalence of positive antibody levels was compared among the transplant groups using a Fisher's exact test. Level of expression of antibodies was evaluated with MFI <500 considered negative, 500-1500 weak, 1500-3000 intermediate and >3000 strong. High resolution HLA typing was performed. Results: Class I antibodies were positive in 24 out of 52 total (46%) with 95% CI: 32% to 61%.14/37 (38%) who underwent transplantation (95% CI: 22% to 55%), 12/27 (44%) undergoing allo transplant, CB (20%), sib (38%), and URD (57%) were positive. The prevalence did not differ significantly among the transplant groups (p=0.3). Class II antibodies were positive in 8 out of 52 total (15%) with 95% CI: 7% to 28%. 5/37 (14%) who underwent transplantation (95% CI: 5% to 29%), 4/27 (15%) undergoing allo transplant, Sib (0%), CB (20%) and URD (21%) were positive. The prevalence did not differ significantly among the transplant groups (p=0.6). In females, 18/28 (64%) were positive for Class I or Class II antibodies of which 5/6 (83%) underwent URD transplants. Persistent antibody levels were detected in 3 of 4 patients tested at day 100 post transplant. Conclusions: Based on this limited pilot study we conclude that there is a high prevalence of anti-HLA antibodies present in recipients at the time of HSC transplantation. However detection of such antibodies did not jeopardize engraftment from various donor sources when HLA donor specific reactions are excluded. Bray et al showed higher incidence of graft failure associated with DSA. Takanashi et al showed that in CB transplants, antibodies were not significant unless the corresponding HLA was present in the CB unit. Based on these studies, we excluded donors with corresponding HLA. All but one patient, in whom donor specific anti-HLA antibodies were identified, achieved sustained marrow engraftment. The long term implications of antibody evolution and specificity to sustained marrow engraftment, graft vs. host and graft vs. tumor effects remain to be clarified. A larger prospective study will need to be conducted to definitely evaluate these relationships including our own which is currently under way. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5957-5964 ◽  
Author(s):  
Stefan O. Ciurea ◽  
Peter F. Thall ◽  
Xuemei Wang ◽  
Sa A. Wang ◽  
Ying Hu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Failure ◽  
Solid Phase ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Hematopoietic Stem

AbstractAnti-HLA donor-specific Abs (DSAs) have been reported to be associated with graft failure in mismatched hematopoietic stem cell transplantation; however, their role in the development of graft failure in matched unrelated donor (MUD) transplantation remains unclear. We hypothesize that DSAs against a mismatched HLA-DPB1 locus is associated with graft failure in this setting. The presence of anti-HLA Abs before transplantation was determined prospectively in 592 MUD transplantation recipients using mixed-screen beads in a solid-phase fluorescent assay. DSA identification was performed using single-Ag beads containing the corresponding donor's HLA-mismatched Ags. Anti-HLA Abs were detected in 116 patients (19.6%), including 20 patients (3.4%) with anti-DPB1 Abs. Overall, graft failure occurred in 19 of 592 patients (3.2%), including 16 of 584 (2.7%) patients without anti-HLA Abs compared with 3 of 8 (37.5%) patients with DSA (P = .0014). In multivariate analysis, DSAs were the only factor highly associated with graft failure (P = .0001; odds ratio = 21.3). Anti-HLA allosensitization was higher overall in women than in men (30.8% vs 12.1%; P < .0001) and higher in women with 1 (P = .008) and 2 or more pregnancies (P = .0003) than in men. We conclude that the presence of anti-DPB1 DSAs is associated with graft failure in MUD hematopoietic stem cell transplantation.

scholarly journals Management of Donor-Specific Antibodies in Haploidentical Transplant: Multicenter Experience From the Madrid Group of Hematopoietic Transplant

2021 ◽  
Vol 12 ◽  
Author(s):  
Rebeca Bailén ◽  
José Luis Vicario ◽  
Laura Solán ◽  
Irene Sánchez-Vadillo ◽  
Pilar Herrera ◽  
...  
Keyword(s):  
Solid Phase ◽  
Hla Class I ◽  
Progressive Increase ◽  
Buffy Coat ◽  
Class I ◽  
Hematopoietic Stem ◽  
Specific Antibodies ◽  
Single Antigen ◽  
Donor Specific Antibodies ◽  
Neutrophil Engraftment

BackgroundDonor specific antibodies (DSAs) can be responsible for graft failure (GF) in the setting of mismatched hematopoietic stem cell transplantation (HSCT). The aim of our study is to report the experience of the Madrid Group of Hematopoietic Transplant (GMTH) in patients with DSAs undergoing haplo-HSCT.MethodsPatients undergoing haplo-HSCT in centers from the GMTH from 2012 to 2020 were included in the study. DSAs were analyzed with a solid-phase single-antigen immunoassay; monitoring was performed during desensitization on days -14, -7, 0 and in a weekly basis until neutrophil engraftment. Desensitization strategies varied depending on center experience, immunofluorescence intensity, complement fixation and type of antibodies.ResultsWe identified a total of 20 haplo-HSCT in 19 patients performed with DSAs in 5 centers. 10 (53%) patients presented anti-HLA class I DSAs (6 of them with &gt; 5000 mean fluorescence intensity (MFI)), 4 (21%) presented anti-HLA class II (1 with &gt; 5000 MFI) and 5 (26%) presented both anti-HLA class I and II (5 with &gt; 5000 MFI). 90% of patients received at least two treatments as desensitization strategy and all experienced a decrease of MFI after desensitization (mean reduction 74%). Only one patient who developed progressive increase of MFI after infusion developed GF. Desensitization treatments used included rituximab, immunoglobulins, therapeutic plasma exchange, incompatible platelets, buffy coat and immunosuppressors. Seventeen (90%) patients achieved neutrophil engraftment; one patient died before engraftment because of infection and one patient with class I DSAs developed primary GF despite an intensive desensitization. After a median follow-up of 10 months, OS and EFS were 60% and 58%, respectively, cumulative incidence of relapse was 5% and NRM was 32%.ConclusionsDespite the optimal strategy of DSAs desensitization remains unclear, the use of desensitization treatment guided by DSAs intensity kinetics constitute an effective approach with high rates of engraftment for patients with DSAs in need for an haplo-HSCT lacking an alternative suitable donor.

Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation From HLA-Mismatched Unrelated Donors

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4475-4475
Author(s):  
Anna Koclega ◽  
Miroslaw Markiewicz ◽  
Urszula Siekiera ◽  
Alicja Dobrowolska ◽  
Sylwia Mizia ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hla Antigens ◽  
Class I ◽  
Hla Antibodies ◽  
Hematopoietic Stem ◽  
Unrelated Donors

Abstract Abstract 4475 Introduction: Anti-HLA Antibodies (Abs) are considered an important factor in solid organ transplants and transfusion medicine, but role of humoral arm of immunological response to HLA antigens in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unknown. Large polymorphism and immunogenicity of HLA-antigens and heterogeneity of anti-HLA Abs warrant the need of such investigation. The purpose of this study was to define presence and profiles of anti-HLA Abs detected before or after allo-HSCT from HLA-mismatched unrelated donors and their impact on allo-HSCT results. Material and methods: 35 HLA-mismatched donor/recipient pairs entered the study. Indication for allo-HSCT was: ALL (7pts), AML(18pts), CML(5pts), SAA(2pts), CLL(1pt), MDS(1pt) and PNH (1pt). Preparative regimen was myeloablative in 33pts (94.3%) and reduced in 2pts (5.7%). Standard GVHD prophylaxis consisted of cyclosporine, methotrexate and pre-transplant anti-thymocyte globulin (34pts) or Alemtuzumab (1pt). HLA A, B, C, DR, DQ alleles were PCR-typed. 21(60%) pts had mismatch of single HLA-antigen: A-4(11.4%), B-1(2.8%), C-13(37%), DQ-3(8,5%); 10(28.5%) pts had mismatch of single HLA-allele: A-3(8.5%), B(11.4%), DQ-3(8.5%); 4 pts had double antigenic (A+C and A+DQ) or combined antigenic/allelic (A/B and C/A) HLA mismatches. Anti-HLA A, B, C, DR, DQ, DP Abs were identified in sera collected before start of the conditioning treatment and +30 days, +100 days and 1 year after allo-HSCT with use of automated DynaChip assay utilizing microchips bearing purified class I and class II HLA antigens. Results: Anti-HLA Abs pre-formed before allo-HSCT were detected in 17(48.5%) pts: against class I, II or both in 6(35%), 4(24%) and 7(41%) pts. Anti-HLA Abs were detected after allo-HSCT in 25(71.4%) pts, against class I, II or both in 9(36%), 3(12%) and 13(52%) pts, respectively. In 7 pts anti-HLA Abs were not detected neither before nor after allo-HSCT. Anti-HLA Abs directed against the mismatched HLA antigens were observed in 4 pts before and in 10 pts after allo-HSCT, no anti-HLA Abs specific against mismatched alleles were detected. Allo-HSCT results obtained in studied subgroups are presented in the Table below: Conclusions: Our preliminary results indicate that anti-HLA Abs are present pre- or post-transplant in mismatched allo-HSCT recipients and may be potentially responsible for the occurrence of complications, what needs to be further investigated and analyzed. Disclosures: No relevant conflicts of interest to declare.

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