Bone Marrow Research

Bone Marrow Research / 2012 / Article
Special Issue

Biological and Genetic Aspects of Donor-Recipient Matching in HSCT

View this Special Issue

Clinical Study | Open Access

Volume 2012 |Article ID 539825 | https://doi.org/10.1155/2012/539825

Anna Koclega, Miroslaw Markiewicz, Urszula Siekiera, Alicja Dobrowolska, Mizia Sylwia, Monika Dzierzak-Mietla, Patrycja Zielinska, Malgorzata Sobczyk Kruszelnicka, Andrzej Lange, Slawomira Kyrcz-Krzemien, "The Presence of Anti-HLA Antibodies before and after Allogeneic Hematopoietic Stem Cells Transplantation from HLA-Mismatched Unrelated Donors", Bone Marrow Research, vol. 2012, Article ID 539825, 7 pages, 2012. https://doi.org/10.1155/2012/539825

The Presence of Anti-HLA Antibodies before and after Allogeneic Hematopoietic Stem Cells Transplantation from HLA-Mismatched Unrelated Donors

Academic Editor: Bronwen Shaw
Received26 Jun 2012
Revised17 Sep 2012
Accepted18 Sep 2012
Published24 Oct 2012

Abstract

Although anti-human leukocyte antigen antibodies (anti-HLA Abs) are important factors responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complications, their role in allogeneic hematopoietic stem cell transplantation (allo-HSCT) has not been finally defined. Enormous polymorphism of HLA-genes, their immunogenicity and heterogeneity of antibodies, as well as the growing number of allo-HSCTs from partially HLA-mismatched donors, increase the probability that anti-HLA antibodies could be important factors responsible for the treatment outcomes. We have examined the incidence of anti-HLA antibodies in a group of 30 allo-HSCT recipients from HLA-mismatched unrelated donors. Anti-HLA Abs were identified in sera collected before and after allo-HSCT. We have used automated DynaChip assay utilizing microchips bearing purified class I and II HLA antigens for detection of anti-HLA Abs. We have detected anit-HLA antibodies against HLA-A, B, C, DR, DQ and DP, but no donor or recipient-specific anti-HLA Abs were detected in the studied group. The preliminary results indicate that anti-HLA antibodies are present before and after allo-HSCT in HLA-mismatched recipients.

1. Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment of both congenital and acquired disturbances of hematopoiesis, especially of hematological malignancies.

The selection of the optimal donor is based on high-resolution HLA typing. The MHC (Major Histocompatibility Complex) contains more than 200 genes which are situated on the short arm of chromosome 6 at 6p21.3. It is divided into three main regions: HLA class I (containing HLA-A, B, and C genes), class II (containing HLA-DR, DQ, and DP genes), and class III region. The role of HLA molecules is to present peptides to T cells (both CD4 and CD8 T cells), enabling them to recognize and eliminate “foreign” particles and also to prevent the recognition of “self” as foreign. HLA mismatches may occur at antigenic or allelic level; the first are characterized by amino acid substitutions in both peptide-binding and T-cell recognition regions, whereas the latter are characterized by amino-acid substitution in the peptide binding regions only [1].

HLA antigens are recognized by immunocompetent T cells, what may lead to graft failure, graft versus host disease (GVHD), and other posttransplant complications as well as to favorable graft versus leukemia (GVL) effect. HLA molecules bear multiple antigenic epitopes, many of which are the so-called “public” epitopes that are shared among the products of several different HLA alleles, resulting in the apparent cross-reactive groups of antigens (CREGs). These shared epitopes may be responsible for patient’s sensitization to multiple HLA antigens, despite a single antigen mismatch only [24].

The participation of cellular arm of immunological response to HLA antigens is well known, but the role of humoral arm of immunity is also very interesting, especially when we consider the enormous polymorphism of HLA-genes, their immunogenicity and huge heterogeneity of antibodies. Antibodies are glycoproteins that belong to the super-family of immunoglobulins [5]. The basic structural units of antibodies are two heavy chains (α, γ, ε, δ or μ) and two light chains (κ or λ). The type of a heavy chain determines the class of antibody: IgA, IgG, IgM, IgE or IgM [6]. The region of chromosome that encodes the antibody is large and contains several distinct genes. The locus containing heavy chain genes is found on chromosome 14; loci containing κ and λ light chain genes are found on chromosomes 2 and 22, respectively. The enormous diversity of antibodies allows the immune system to recognize an equally wide variety of antigens [5]. It has been known that humans produce about 10 billion different antibodies capable of binding a distinct epitope of an antigen [7]. Such a diversity of antibodies is caused by domain variability, recombination, somatic hypermutation and affinity maturation, class switching, and affinity designations [810]. Anti-HLA Abs may be present in healthy individuals [11, 12]. The sensitization to MHC antigens may be caused by transfusions, pregnancy, or failed previous grafts [13]. Anti-HLA Abs are more frequently detected in patients with hematological disorders due to their alloimmunization, resulting mainly from common use of transfusions [14].

The clinical significance of anti-HLA Abs is well known in the field of transfusional medicine. The presence of anti-HLA Abs in patients is one of the major causes of platelet transfusion refractoriness [15]. On the other hand, anti-HLA Abs present in blood products have been shown to be a major cause of transfusion-related acute lung injury (TRALI) [16, 17]. The role of anti-HLA Abs is also well known in solid organ transplantation—especially in kidney transplantation, because transplanted kidneys are highly susceptible to antibody-mediated injury [18, 19]. Antibodies produced before kidney transplantation (reacting with donor’s HLA antigens) induce hyperacute or acute vascular rejections which frequently result in transplant failure [20, 21].

Despite the well-recognized role of antibody-mediated rejection in solid organ transplantation, the graft rejection following allo-HSCT is generally attributed to cytolitic host-versus-graft (HVG) reaction mediated by host T and NK cells, that survived the conditioning regimen [2225]. Engraftment failure rate is approximately 4% in allo-HSCT from matched unrelated donor (MUD) and about 20% in cord blood or T-cell-depleted haploidentical transplantations [26, 27]. Antibody-mediated bone marrow failure after allogeneic bone marrow transplantation can be also caused by antibody-dependent cell-mediated cytotoxicity (ADCC), or complement-mediated cytotoxicity [2830]. In ADCC, the cytotoxic destruction of antibody-coated target cells by host cells is triggered when an antibody bound to the surface of a cell interacts with Fc receptors on NK cells or macrophages. Preformed antibodies present at the time of hematopoietic stem cell infusion are unaffected by standard transplantation conditioning regimens, T- or B-cell immunosuppressive drugs or modulatory strategies given in the pretransplantation period [31].

Albeit the T-cell-mediated cellular immunity is the primary barrier for bone marrow allorejection in nonsensitized recipients in the animal models (mice), the humoral arm of the immune response plays a very important, previously unappreciated, role in the rejection of allogeneic stem cell transplantation in sensitized mice and in such case the rejection of a bone marrow is T-cell independent [31, 32]. Moreover, the achievement of a mixed allogeneic chimerism resulted in reverse of the sensitization in allosensitized recipients [30, 33]. Probably not only antigen-specific but also cross-reactive or broadly reactive alloantibodies may be responsible for the graft failure [32]. Spellman and Bray have demonstrated in a retrospective, case-controlled study that the prevalence of donor-specific anti-HLA antibodies was higher in a group of mismatched unrelated donor recipients who suffered graft rejection than in a control group that engrafted. Among the 37 recipients who failed to engraft 9 (24%) possessed DSAS against HLA-A, B, or DP, but only 1 (1%) recipient of 78 controls did [34]. In the study of Ciurea et al. DSAS was the single most important factor associated with graft failure and HLA-mismatches increased the occurrence of donor-specific HLA antibodies in MUD transplantation [35]. Takanashi et al. demonstrated the impact of anti-HLA antibodies on engraftment after myeloablative single unit cord blood transplantation. Patients with anti-HLA antibodies experienced slower neutrophils and platelet recovery than antibody-free patients. Although no effect of anti-HLA antibodies on GvHD grade II-IV, relapse, or TRM has been observed, the overall and event-free survival were significantly inferior in antibody-positive patients [36]. Similar observations were made after double umbilical cord blood transplantation [37].

As presented above, the influence of anti-HLA Abs, including Abs directed against mismatched antigens, on the results of allo-HSCT, especially on graft failure, has been proved in several reports. However, in patients following allo-HSCT, the series of time remote complications may occur. As antibodies appearing in the result of the earlier immunization are detected before transplantation, the question of their presence and specificity after transplant, after the myeloablative conditioning treatment, and during administration of immunosuppressive therapy is open, when the hematopoietic function is taken over by the donor’s cells. The first cells to reconstitute (within the first 100 days) after the transplantation are granulocytes, monocytes, macrophages, and NK cells. In contrast, T and B lymphocytes remain severely reduced and their function is impaired from 6 months to 1 year after the transplantation [1].

Therefore, the aim of our study was to examine the presence and the specificity of anti-HLA antibodies before and following the allo-HSCT.

2. Materials and Methods

We included 30 patients who received allo-HSCT from partially HLA-mismatched unrelated donors and who agreed to participate in the study. Donors lacking full HLA compatibility with recipients were chosen when compatible donors were not available. Standard high-resolution allelic typing of HLA-A, B, C, DRB1, and DQB1, without HLA-DP, was performed. The study was carried out in the Department of Hematology and Bone Marrow Transplantation of the Medical University of Silesia in Katowice, Poland, between 2007 and 2011. The examination of patient’s sera was scheduled at 4 time points: before the start of conditioning treatment and 30 days, 100 days, and 1 year after transplant.

The preparative treatment was myeloablative in 28 (93%) and reduced in 2 (7%) pts. Standard GVHD prophylaxis consisted of pretransplant antithymocyte globulin, cyclosporine A in initial dose 3 mg/kg i.v. starting from day −1 with dose adjusted to its serum level and shift to oral administration about day +20, methotrexate 15 mg/m2 i.v. on day +1, and 10 mg/m2 i.v. on days +3 and +6. Methylprednisolone at dose 2 mg/kg i.v. was the first line therapy of aGVHD symptoms; in few patients mycophenolate mofetil or tacrolimus was used. The source of cells was the bone marrow in 9 (30%) and peripheral blood in 21 (70%) patients.

The detailed characteristics of the study population are presented in Table 1.


Median age (range)
 Recipient37 (13–57) years
 Donor36 (19–55) years
Mean time from diagnosis to allo-HSCT
(range)
0.75 (0.63–10.3) years

Number (%)

Sex
 Donor
  Male19 (63.3%)
  Female11 (36.7%)
 Recipient
  Male16 (53.3%)
  Female14 (46.7%)
 Sex matching
  Male donor, male recipient10 (33.3%)
  Female donor, female recipient5 (16.6%)
  Male donor female recipient9 (30%)
  Female donor, male recipient6 (20%)
HLA- mismatch
 Antigen A4 (13.3%)
 Antigen C12 (40%)
 Antigen DQ2 (6.6%)
 Allele A2 (6.6%)
 Allele B5 (16.6%)
 Allele DQ3 (10%)
 Antigen B + Antigen C1 (3.3%)
 Antigen A + Allele B1 (3.3%)
Primary indication for allo-HSCT
 Acute lymphoblastic leukemia (ALL)6 (20%)
 Acute myeloid leukemia (AML)15 (20%)
 Chronic myeloid leukemia (CML)5 (16.6%)
 Chronic lymphocytic leukemia (CLL)1 (3.3)
 Severe aplastic anemia (SAA)2 (6.6%)
 Paroxysmal nocturnal hemoglobinuria (PNH)1 (3.35)
Preparative regimen
 Cyclophosphamide1 (3.3%)
 TBI + Cyclophosphamide6 (20%)
 TBI + Fludarabine1 (3.3%)
 Treosulfan + Fludarabine6 (20%)
 Busulfan + Cyclophosphamide12 (40%)
 Busulfan + Fludarabine1 (3.3%)
 Treosulfan + Cyclophosphamide1 (3.3%)
 Busulfan + Cyclophosphamide + Gemtuzumab Ozogamycin1 (3.3%)
 Rituximab + Alemtuzumab + Melphalan1 (3.3%)
Immunosuppressive treatment
 Glycocorticoid27 (90%)
 Cyclosporine30 (100%)
 Mycophenolate mofetil7 (23%)
 Tacrolimus1 (3.3%)
Source of cells
 Bone marrow9 (30%)
 Peripheral blood21 (70%)

Patient’s sera were tested for the presence of anti-HLA Abs in the HLA and Immunogenetics Laboratory of Regional Blood Center in Katowice, Poland. Anti-HLA A, B, C, DR, DQ, and DP antibodies were detected and identified using the ELISA-based DynaChip Technology. The DynaChip HLA Antibody analysis system utilizes microchips spotted with purified HLA antigens immobilized on the surface of the glass chip. Test serum was free of aggregates and excess lipids before testing. This was achieved by centrifugation for 10 minutes at 10,000 g. The clarified supernatant was diluted with the Sample Diluent contained within the kit and then it was added to the DynaChip wells. Anti-HLA Abs present in the test serum were bound to the HLA antigens on the surface on the chip. Bound antibodies were then detected using the Antibody Detection Reagent (antihuman IgG and horseradish peroxidase complex). The assay was completed with colorimetric detection. The resulting patterns of blue-positive and clear-negative spots were recorded by the software and subsequently automatically analyzed by the DynaChip Analysis Software. The presence of at least one anti-HLA antibody was regarded as presence of anti-HLA Abs, whereas if the examined serum contained antibodies against more than 50 different HLA antigens they were regarded as “anti-HLA Abs to many specificities.” Applied DynaChip HLA Antibody analysis system did not allow to measure the concentration of detected antibodies.

The study has been approved by the responsible Ethical Committee of Medical University of Silesia.

3. Results

Anti-HLA Abs were detected in 26 (86.6%) patients. Anti-HLA Abs against HLA class I, II, or both were detected in 8 (26.6%), 2 (6,6%), or 16 (53.3%) patients, respectively. In 4 (13.3%) patients they were detected before transplant only, in 10 (33.3%) patients after transplant only, and in 12 (40%) patients both before and after transplantation. In 4 (13.3%) patients anti-HLA Abs were not detected neither before nor after allo-HSCT. Anti-HLA Abs directed against the class or antigens of mismatched HLA were detected in 4 patients before transplant and in 9 patients after transplant. In 5 patients we identified antibodies with the same specificities before and 30 days after the transplantation (as presented in Table 2, cases’ numbers: 19, 20, 21, 23, and 30). Although we did not identify neither donor or recipient allele-specific anti-HLA Abs, antibodies that detected after transplant in 3 patients belonged to the same CREG (Cross-Reactive Group) as recipient’s mismatched HLA antigen (as presented in Table 2, cases’ numbers: 19-10CREG, 24-5CREG, and 29-12CREG). These antibodies were detected more than 100 days after transplantation, so it is very likely that they were produced by donor cells.


NoTyping of mismatched HLADetected anti-HLA Abs with regard to allo-HSCT
RecipientDonor HLA-mismatchBefore+30 days+100 days+1 year

1C 0401C 12XXAntigen CMany specificitiesNot testedDR15Not tested
C 0501C 0501
2DQB1 0202DQB1 0202Allele DQB1Many specificitiesNot testedB70Not tested
DQB1 0302DQB1 0301
3C 0802C 0802Antigen CMany specificitiesNot testedNot testedNot detected
C 1203C 0303
4C 0501C 0201Antigen CNot detectedB65, B46, B37, C36, C10DRB1*15, DQB1*06Not detected
C 0702C 0702
5A 0201A 0201Allele A
Not detectedNot detectedNot testedC14, B62, C9, A26
A 0302A 0301
6C 0401C 0401Antigen CNot detectedNot testedMany specificitiesNot detected
C 1602C 1502
7C 0802C 0702Antigen CNot detectedNot testedMany specificitiesNot detected
C 1502C 0702
8DQB1 0202DQB1 0303Antigen DQB1Not detectedNot testedNot detectedNot detected
DQB1 0301DQB1 0301
9C 0303C 0403Antigen CNot detectedNot testedDR13B82, B49
C 0102C 0102
10C 0303
C 0401
C 0401
Antigen CA23, A24, B27, B35, B38, B40, C0803, C0804Not testedB45, A66DQ8, DR4
11C 0303C 0403Antigen CB75, B46, DR13, DQ3Not testedNot detectedNot detected
C 0602C 0602
12DQB1 0301DQB1 0301Allele DQB1Not detectedNot testedNot detectedB82, A34, DQ8, DR4
DQB1 0504DQB1 0501
13C 0202C 0202Antigen CNot detectedNot testedNot testedB70
C 0102C 0202
14DQB1 0602DQB1 0602Allele DQB1Many specificitiesMany specificitiesNot detectedNot detected
DQB1 0602DQB1 0603
15C 0102
C 0602
C 0302
C 0602
Antigen CNot detectedC18, DRB3*, DPB1*05, DRB104, DQB1*06Not testedNot tested
16A 1101A 24xxAntigen ANot detectedNot detectedNot testedDQ2, DQ4, DQA02, DQA04
A 2601A 2601
17A 0205A 0201Allele ADQB1*03, DRB1*04Not detectedNot testedNot tested
A 2402A 2402
18B 4102B 4102Antigen B, antigen CNot detectedNot detectedNot detectedNot tested
B 5601B 5501
C 0401C 0301
C 1703C 1703
19A 2601A 0201Antigen ADQ8, DR4DQ8, DR4Not detectedB45, A66, DR10, DR12
A 3201A 3201
20DQB1 0301DQB1 0301Antigen DQB1A2, 2C
A0302, B67
A2, C2, B67A2, DR 16Not tested
DQB1 0302DQB1 0402
21A 0201
A 2901
A 0205
A 2901
Allele AB7, 7C, B60, B81, A2403, A2608, C0727, C0804B7B47, B63Not tested
22C 0501C 0501Antigen CNot detectedNot detectedNot detectedNot detected
C 1203
23C 0304
C 0702

C 0702
Antigen CA2 A0302, B2703, B3501, B3503, 4006, B4101, B45, B4604, B67, B76, B78, C0103, C0403, DR51, DR15, DQ6, DR16, DQA01
DPB39, DPB3901, DPB85, DPB8501, DQB0502
A2, A0207, A0302, B2703, B3503, B4006, B4101, B67, B76, C0403, DR51, DR15, DQ6, DR16 DPB39, DPB3901, DPB85, DPB8501, DQB0502A2, DR51, DR16DQ7, DQA05
24B 3501B 3503Allele BB42, A80, C17Not detectedB77Not detected
B 5701B 5701
25A 2402A 03xxAntigen ANot detectedNot detectedNot detectedNot tested
A 26012601
26B 3501B 3501Allele BC7, DQ8Not detectedNot detectedNot detected
B 3502B 35xx
27A 3001A 01xxAntigen ADR10, DR11B77, B38Not detectedNot tested
A 3101
28A 2501A 2501Antigen ANot detectedB77, A36Not detectedNot detected
A 3201A 23xx
29B 1801B 1801Allele BA31Not detectedB61, C15, B35Not tested
B 4402B 4427
30B 3503
B 3501
B 3503
B 3503
Allele BDQ5, DQ6, DQA01C7, DQ6,
DR51,
DPB39,
DPB3901,
DPB85,
DPB8501,
DQB0502,
C7, DR 51, DPB14, DPB1401, DQB0502, DQB0602, DQB0608, DR0806, DR2, DQ6, DQA01Not tested

The specificities of anti-HLA Abs detected before allo-HSCT and at different time-points after transplant are presented in Table 2. We have succeed only partially in consequent collecting sera at all scheduled timepoints from patients included into the study for analysis due to the fact that some patients were referred to our center for allo-HSCT from remote parts of Poland. After allo-HSCT they have moved for care to their home centers and collection of the complete set of sera from them was impossible.

4. Conclusions

Our preliminary results indicate that preformed anti-HLA Abs can be detected before and may also appear after transplant in mismatched allo-HSCT recipients. Anti-HLA Abs present in 3 patients were directed against HLA antigens which belonged to the same serological Cross Reactive Groups as the mismatched HLA antigens.

In 5 patients anti-HLA Abs directed against the same HLA antigen were detected before and after allo-HSCT what may indicate that they were not destroyed during the myeloablative conditioning treatment and standard immunosuppressive therapy. These antibodies belonged to the same serological Cross Reactive Group as the recipient’s but not donor’s mismatched HLA antigens, so it is possible to conclude that donor’s cells may produce anti-HLA Abs against the recipients cells after allo-HSCT. Therefore, they may theoretically be responsible for induction of several immunological posttransplant complications. Antibodies detected after transplantation may also result from immunization, for example, by transfusions, as allo-HSCT recipients often require intensive supportive treatment with blood derivatives.

We believe that our observations help to better understand the immune mechanisms contributing to allogeneic sensitization which may influence allo-HSCT results. It is possible that sensitized patients who possess anti-HLA antibodies before or after the transplantation could benefit from modification of conditioning and immunosuppressive therapeutic approaches in the future.

Presented preliminary outcomes of 30 patients are based only on part of our whole study group which consists of 70 patients. The statistical analysis aimed to reveal the eventual impact of anti-HLA Abs on allo-HSCT results will be performed after completion and examination of sera taken at all scheduled timepoints from the whole group. We also consider the extension of the search for anti-HLA Abs with utilization of Luminex Labscreen method which enables to calculate the mean fluorescence intensity and thus to assess the concentration of detected antibodies.

Conflict of Interests

The authors report having no conflict of interests.

References

  1. J. Apperley, E. Carreras, E. Gluckman, and T. Masszi, Haematopoietic Stem Cell Transplantation-The EBMT Handbook, 6th edition, 2012.
  2. F. Legrand and J. Dausset, “Serological evidence of the existence of several antigenic determinants (or factors) on the HLA-A gene products,” in Histocompatibility Testing 1972, J. Dausset and J. Colombani, Eds., Munksgaard, Copenhagen, Denmark, 1973. View at: Google Scholar
  3. G. E. Rodey and T. C. Fuller, “Public epitopes and the antigenic structure of the HLA molecules,” Critical reviews in immunology, vol. 7, no. 3, pp. 229–267, 1987. View at: Google Scholar
  4. B. D. Schwartz, L. K. Luehrman, and G. E. Rodey, “Public antigenic determinant on a family of HLA-B molecules. Basis for cross-reactivity and a possible link with disease predisposition,” Journal of Clinical Investigation, vol. 64, no. 4, pp. 938–947, 1979. View at: Google Scholar
  5. R. A. Rhoades and R. G. Pflanzer, Human Physiology, Thomson Learning, Stockholm, Sweden, 4th edition, 2002.
  6. J. Charles, Immunobiology, Garland Publishing, New York, NY, USA, 5th edition, 2001.
  7. L. J. Fanning, A. M. Connor, and G. E. Wu, “Development of the immunoglobulin repertoire,” Clinical Immunology and Immunopathology, vol. 79, no. 1, pp. 1–14, 1996. View at: Publisher Site | Google Scholar
  8. P. Peter, The Immune System, Garland Science, New York, NY, USA, 2nd edition, 2005.
  9. Y. Bergman and H. Cedar, “A stepwise epigenetic process controls immunoglobulin allelic exclusion,” Nature Reviews Immunology, vol. 4, no. 10, pp. 753–761, 2004. View at: Publisher Site | Google Scholar
  10. M. Or-Guil, N. Wittenbrink, A. A. Weiser, and J. Schuchhardt, “Recirculation of germinal center B cells: a multilevel selection strategy for antibody maturation,” Immunological Reviews, vol. 216, no. 1, pp. 130–141, 2007. View at: Publisher Site | Google Scholar
  11. N. El-Awar, P. I. Terasaki, A. Nguyen et al., “Epitopes of human leukocyte antigen class I antibodies found in sera of normal healthy males and cord blood,” Human Immunology, vol. 70, no. 10, pp. 844–853, 2009. View at: Publisher Site | Google Scholar
  12. L. E. Morales-Buenrostro, P. I. Terasaki, L. A. Marino-Vázquez, J. H. Lee, N. El-Awar, and J. Alberú, “Natural human leukocyte antigen antibodies found in nonalloimmunized healthy males,” Transplantation, vol. 86, no. 8, pp. 1111–1115, 2008. View at: Publisher Site | Google Scholar
  13. W. E. Braun, “Laboratory and clinical management of the highly sensitized organ transplant recipient,” Human Immunology, vol. 26, no. 4, pp. 245–260, 1989. View at: Publisher Site | Google Scholar
  14. A. Idica, N. Sasaki, S. Hardy, and P. Terasaki, “Unexpected frequencies of HLA antibody specificities present in sera of multitransfused patients.,” Clinical transplants, pp. 139–159, 2006. View at: Google Scholar
  15. E. Hod and J. Schwartz, “Platelet transfusion refractoriness,” British Journal of Haematology, vol. 142, no. 3, pp. 348–360, 2008. View at: Publisher Site | Google Scholar
  16. R. A. Middelburg, D. Van Stein, E. Briët, and J. G. Van Der Bom, “The role of donor antibodies in the pathogenesis of transfusion-related acute lung injury: a systematic review,” Transfusion, vol. 48, no. 10, pp. 2167–2176, 2008. View at: Publisher Site | Google Scholar
  17. A. Reil, B. Keller-Stanislawski, S. Günay, and J. Bux, “Specificities of leucocyte alloantibodies in transfusion-related acute lung injury and results of leucocyte antibody screening of blood donors,” Vox Sanguinis, vol. 95, no. 4, pp. 313–317, 2008. View at: Publisher Site | Google Scholar
  18. E. R. Vasilescu, E. K. Ho, A. I. Colovai et al., “Alloantibodies and the outcome of cadaver kidney allografts,” Human Immunology, vol. 67, no. 8, pp. 597–604, 2006. View at: Publisher Site | Google Scholar
  19. A. A. Zachary, L. E. Ratner, J. A. Graziani, D. P. Lucas, N. L. Delaney, and M. S. Leffell, “Characterization of HLA class I specific antibodies by ELISA using solubilized antigen targets: II. Clinical relevance,” Human Immunology, vol. 62, no. 3, pp. 236–246, 2001. View at: Publisher Site | Google Scholar
  20. F. Kissmeyer-Nielsen, S. Olsen, V. P. Petersen, and O. Fjeldborg, “Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells.,” The Lancet, vol. 2, no. 7465, pp. 662–665, 1966. View at: Google Scholar
  21. G. M. Williams, D. M. Hume, R. P. Hudson Jr, P. J. Morris, K. Kano, and F. Milgrom, “Hyperacute renal-homograft rejection in man.,” New England Journal of Medicine, vol. 279, no. 12, pp. 611–618, 1968. View at: Google Scholar
  22. E. Schwartz, T. Lapidot, and D. Gozes, “Abrogation of bone marrow allograft resistance in mice by increased total body irradiation correlates with eradication of host clonable T cells and alloreactive cytotoxic precursors,” Journal of Immunology, vol. 138, no. 2, pp. 460–465, 1987. View at: Google Scholar
  23. D. A. Vallera and B. R. Blazar, “T cell depletion for graft-versus-host disease prophylaxis: a perspective on engraftment in mice and humans,” Transplantation, vol. 47, no. 5, pp. 751–760, 1989. View at: Google Scholar
  24. K. Fleischhauer, N. A. Kernan, R. J. O'Reilly, B. Dupont, and S. Y. Yang, “Bone marrow-allograft rejection by T lymphocytes recognizing a single amino acid difference in HLA-B44,” New England Journal of Medicine, vol. 323, no. 26, pp. 1818–1822, 1990. View at: Google Scholar
  25. J. Pei, Y. Akatsuka, C. Anasetti et al., “Generation of HLA-C-specific cytotoxic T cells in association with marrow graft rejection: analysis of alloimmunity by T-cell cloning and testing of T-cell-receptor rearrangements,” Biology of Blood and Marrow Transplantation, vol. 7, no. 7, pp. 378–383, 2001. View at: Google Scholar
  26. S. M. Davies, C. Kollman, C. Anasetti et al., “Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program,” Blood, vol. 96, no. 13, pp. 4096–4102, 2000. View at: Google Scholar
  27. P. Rubinstein, C. Carrier, A. Scaradavou et al., “Outcomes among 562 recipients of placental-blood transplants from unrelated donors,” New England Journal of Medicine, vol. 339, no. 22, pp. 1565–1577, 1998. View at: Publisher Site | Google Scholar
  28. C. Anasetti, K. C. Doney, and R. Storb, “Marrow transplantation for severe aplastic anemia. Long-term outcome in fifty 'untransfused' patients,” Annals of Internal Medicine, vol. 104, no. 4, pp. 461–466, 1986. View at: Google Scholar
  29. R. P. Warren, R. Storb, P. L. Weiden, P. J. Su, and E. D. Thomas, “Lymphocyte-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity in patients with aplastic anemia: distinguishing transfusion-induced sensitization from possible immune-mediated aplastic anemia.,” Transplantation Proceedings, vol. 13, no. 1, pp. 245–247, 1981. View at: Google Scholar
  30. Y. L. Colson, M. J. Schuchert, and S. T. Ildstad, “The abrogation of allosensitization following the induction of mixed allogeneic chimerism,” Journal of Immunology, vol. 165, no. 2, pp. 637–644, 2000. View at: Google Scholar
  31. P. A. Taylor, M. J. Ehrhardt, M. M. Roforth et al., “Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients,” Blood, vol. 109, no. 3, pp. 1307–1315, 2007. View at: Publisher Site | Google Scholar
  32. R. J. Greenwald, G. J. Freeman, and A. H. Sharpe, “The B7 family revisited,” Annual Review of Immunology, vol. 23, pp. 515–548, 2005. View at: Publisher Site | Google Scholar
  33. A. Bartholomew, D. Sher, S. Sosler et al., “Stem cell transplantation eliminates alloantibody in a highly sensitized patient,” Transplantation, vol. 72, no. 10, pp. 1653–1655, 2001. View at: Google Scholar
  34. S. Spellman, R. Bray, S. Rosen-Bronson et al., “The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure,” Blood, vol. 115, no. 13, pp. 2704–2708, 2010. View at: Publisher Site | Google Scholar
  35. S. O. Ciurea, P. F. Thall, X. Wang et al., “Donor-specific anti-HLAAbs and graft failure in matched unrelated donor hematopoietic stem cell transplantation,” Blood, vol. 118, no. 22, pp. 5957–5964, 2011. View at: Publisher Site | Google Scholar
  36. M. Takanashi, Y. Atsuta, K. Fujiwara et al., “The impact of anti-HLA antibodies on unrelated cord blood transplantations,” Blood, vol. 116, no. 15, pp. 2839–2846, 2010. View at: Publisher Site | Google Scholar
  37. C. Cutler, H. T. Kim, L. Sun et al., “Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation,” Blood, vol. 118, no. 25, pp. 6691–6697, 2011. View at: Publisher Site | Google Scholar

Copyright © 2012 Anna Koclega et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views3901
Downloads996
Citations

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.