A glow of HLA typing in organ transplantation
© Mahdi; licensee Springer. 2013
Received: 12 January 2013
Accepted: 15 February 2013
Published: 23 February 2013
The transplant of organs and tissues is one of the greatest curative achievements of this century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the main goal of the immune response is the MHC (major histocompatibility complex) molecules expressed on the surface of donor cells. Cell surface molecules that induce an antigenic stimulus cause the rejection immune response to grafted tissue or organ. A wide variety of transplantation antigens have been described, including the major histocompatibility molecules, minor histocompatibility antigens, ABO blood group antigens and endothelial cell antigens. The sensitization to MHC antigens may be caused by transfusions, pregnancy, or failed previous grafts leading to development of anti-human leukocyte antigen (HLA) antibodies that are important factor responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complication Anti-HLA Abs may be present in healthy individuals. Methods for HLA typing are described, including serological methods, molecular techniques of sequence-specific priming (SSP), sequence-specific oligonucleotide probing (SSOP), Sequence based typing (SBT) and reference strand-based conformation analysis (RSCA) method. Problems with organ transplantation are reservoir of organs and immune suppressive treatments that used to decrease rate of rejection with less side effect and complications.
KeywordsTransplantation Rejection Major histocompatibility
The HLA system includes a complex array of genes located on chromosome number 6 and their molecular products that are involved in immune regulation and cellular differentiation. Human leukocyte antigen (HLA) molecules are expressed on almost all nucleated cells, and they are the major molecules that initiate graft rejection. There are three classical loci at HLA class I: HLA-A, -B, and -Cw, and five loci at class II: HLA-DR, -DQ, -DP, -DM, and -DO. The system is highly polymorphic . The contribution of the allelic diversity of class I and II genes to immune recognition and alloreactivity can be analyzed by serological methods and molecular methods at the DNA level by different methods like sequence specific primer (SSP) and oligotyping with locus- and allele-specific oligonucleotide probes (SSOP) . HLA class I and II matching is important in organ transplantation  especially in kidney and bone marrow transplantation. In heart and lung transplantation, HLA match at the DR locus is important but there is some difficulties like ischemic times, availability of donors and clinical need of recipients. Corneal grafts are not usually influenced by HLA matching, unless being transplanted into a vascularized bed . Transplantation of foreign tissue induces both humoral and cellular immune responses in the recipient, which leads to graft rejection or, for bone marrow transplantation, graft versus host disease (GVHD).
MHC class I proteins form a functional receptor on most nucleated cells of the body. There are 3 major and 3 minor MHC class I genes in HLA: HLA-A,HLA-B and HLA-C; minor genes are HLA-E, HLA-F and HLA-G . β2- microglobulin binds with major and minor gene subunits to produce a heterodimer. There are 3 major and 2 minor MHC class II proteins encoded by the HLA. The genes of the class II combine to form heterodimeric (αβ) protein receptors that are typically expressed on the surface of antigen-presenting cells. Major MHC class II HLA-DP: α-chain encoded by HLA-DPA1 locus and β-chain encoded by HLA-DPB1 locus. HLA-DQ: α-chain encoded by HLA-DQA1 locus and β-chain encoded by HLA-DQB1 locus. The last one is HLA-DR: α-chain encoded by HLA-DRA locus and four β-chains (only 3 possible per person), encoded by HLA-DRB1, DRB3, DRB4, and DRB5 loci. The other MHC class II proteins, DM and DO, are used in the internal processing of antigens, loading the antigenic peptides generated from pathogens onto the HLA molecules of antigen-presenting cell .
Two systems of nomenclature are applied to HLA. The first system is based on serological recognition. In this system, antigens were eventually assigned letters and numbers (e.g., HLA-B51 or, shortened, B51). Modern HLA nomenclature are begin with HLA- and the locus name, then * and even number of digits specifying the allele. The first two digits specify a group of alleles. Older typing methodologies often could not be completely distinguish alleles and so stopped at this level. The third through fourth digits specify a synonymous allele. Digits five through six denote any synonymous mutations within the coding frame of the gene. The seventh and eighth digits distinguish mutations outside the coding region. Letters such as L, N, Q, or S may follow an allele's designation to specify an expression level or other non-genomic data known about it. Thus, a completely described allele may be up to nine digits long, not including the HLA-prefix and locus notation, (e.g., HLA- A*24:02:01 N N=Null) to designate a specific allele at a given HLA locus. Every two years, a nomenclature is put forth to aid researchers in interpreting serotypes to alleles .
The number of variant alleles at class I loci
MHC class I
The number of variant alleles at class II loci
MHC class II
-B3 to -B51
HLA typing and its influence on organ transplantation
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 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 . When a human transplant is performed, HLA (human leukocyte antigens) molecules from a donor are recognized by the recipient's immune system by direct and indirect methods of allorecognition triggering an alloimmune response. Matching of donor and recipient for MHC antigens showed a significant positive effect on graft acceptance . In organ transplantation, the adaptive immunity is the main response exerted to the transplanted tissue, since the main target of the immune response is the MHC molecules expressed on the surface of donor cells. T-cell activation leads to the production of cytokines and chemokines which in turn may recruit components of the innate immunity like NK cells or macrophages and complement . In addition to that, defensins and cathelicidin have chemoattractant properties on T lymphocytes .
In transplantation immunology, the major impact in graft loss comes from the effects of HLA-B and -DR antigens . The effects of HLA-DR mismatches are the most important in the first 6 months after transplantation, the HLA-B effect emerges in the first 2 years, and HLA-A mismatches have a deleterious effect on long-term graft survival .
Techniques of tissue typing
Previously, HLA typing was done by two methods: serologic method using antiserum and mixed lymphocyte culture (MLC). After that a more precise DNA-based HLA typing methods using molecular techniques, such assequence-;specific oligonucleotide probe hybridization (SSOP), sequence-specific primer amplification (SSP), sequencing-based typing (SBT), and reference strand-based conformation analysis (RSCA), have been developed and are frequently used . In 2013, a new project of the 16IHIW demonstrated the potential benefits of next-generation sequencing (NGS) in the HLA laboratory. NGS may resolve the issue through the combination of clonal amplification, which provides phase information, and the ability to sequence larger regions of genes, including introns, without the additional effort or cost associated with current methods . Another simplified method using short tandem repeat (STR) genotyping provided additional information allowing determination of the extent of HLA identity in families where HLA haplotype inheritance was ambiguous, due to extensive homozygosity or shared parental haplotypes. The HLA STR assay is a reliable and rapid test that used inexpensively screen potential sibling donors for HLA identity .
First method is serological assay, can be made by antibody-dependent cell-mediated cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC). |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. Serologic method was also used in screening for HLA antibodies in the recipient. These antibodies are important because they are reactive with lymphocytes of a prospective donor (cross matching) [20, 21].
Concerning the cellular assay, this is a mixed lymphocyte culture and used to determine the HLA class II types. The cellular assay is more sensitive in detecting HLA differences than serotyping. This is because minor differences unrecognized by alloantisera can stimulate T cells. This typing is designated as Dw types [22, 23].
Tissue typing by molecular method, utilizing the sequence-specific oligonucleotide (SSO) and sequence-specific primer (SSP) technologies has been in routine use in many tissue-typing laboratories worldwide for more than 20 years since the development of the polymerase chain reaction. Both methods are very useful for clinical and research purposes and can provide generic (low resolution) to allelic (high resolution) typing results . DNA based method had more sensitivity, accuracy and resolving power than serologic typing methods . Sequencing-based typing (SBT) is a high-resolution method for the identification of HLA polymorphisms. The majority of HLA Class I alleles can be discriminated by their exon 2 and 3 sequence, and for Class II alleles, exon 2 is generally sufficient. There are polymorphic positions in other exons, which may require additional sequencing to exclude certain alleles with differences outside exon 2 and 3, depending on the clinical requirement and relevant accreditation guidelines. Examination of all nucleotides, both at conserved and polymorphic positions enables the direct identification of new alleles, which may not be possible with techniques such as SSP and SSO typing .
Regarding antibodies screening was done to avoid hyperacute rejection, it is very important to identify recipient anti-HLA antibodies to antigens expressed on donor with blood cells . The pioneer method to detect such antibodies is complement-dependent cytotoxicity (CDC), in the mid 1990s, it has been gradually replaced by more-sensitive solid-phase immunoassays (SPI) such as the enzyme-linked immunosorbent assay and the bead-based technology (i.e., flow cytometry: Flow PRA and Flow Analyzer-Luminex). These assays used microparticles coated with purified HLA molecules. Hence, the era of solid-phase microparticle technology for HLA antibody detection was born permitting the sensitive and specific detection of HLA antibody. A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation like SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and in particular the use of the single-antigen bead assay to detect antibodies to HLA loci such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods .
It is hoped that these technologies will ultimately lead to the identification of parameters that best correlate with and/or predict transplant outcomes . However, the new techniques have been associated with decreased specificity, and some non-HLA antigens with no clinical relevance have been able to give a positive cross match . These “false-positive” antibody results have a consequence of decreasing a chance of the patient to receive an organ . Susal and Opelz (2012)  done a collaborative transplant study; they summarized that cold ischemia up to 18 hours was found not to be detrimental for graft outcome, and short cold ischemia did not eliminate the effect of HLA matching  and HLA-DR mismatches were a significant risk factor for posttransplant non-Hodgkin lymphoma and hip fracture [34, 35]. Meier-Kriesche et al. 2009 , who examined some 16,000 renal transplant candidates in the USA that were re-listed after loss of a primary kidney transplant, found that with increasing numbers of HLA mismatches of the first transplant, there was a significant increase in panel reactive antibody. They also observed a pronounced influence of HLA matching on graft outcome in patients with pretransplant HLA antibodies or high serum levels of the T-cell activation marker sCD30 . Although graft survival rates improved greatly now a days, sensitization of the recipient at the B-cell level and development of IgG antibodies still represents a major problem in kidney transplantation that detected in 17% of patients after first transplant by ELISA screening assay and using the more sensitive Luminex technology, HLA antibodies of the IgG, IgM, or IgA isotypes were detected in almost all patients waiting for transplant . Other types of antibodies that directed against non-HLA antigens are important like against graft endothelium , MICA  and Angiotensin type 1 receptor . To reduce such presumed undetected antibody activity below clinically relevant threshold levels peritransplant apheresis was indicated . Heinold et al 2013  reported that HLA compatibility significantly influences the outcome of kidney transplants in sensitized retransplant recipients even at the allele level. In addition to that, the interaction between recipient HLA ligand and donor KIR had a significant impact on the outcome of patients receiving HLA matched sibling .
What are the future prospects for transplantation?
Organ transplants have helped thousands of people. The main obstacles are reservoir of organs, so we need to increase the number of available organs and find more precise methods of immunosuppression in order to prevent rejection without the dangerous side effects of infection and cancer.
Expansion the field of organ and tissue transplantation has accelerated amazingly, since the human major histocompatibility complex (MHC) was discovered in 1967. Transplantation immunology is a very complex process and the numbers of alleles were increased remarkably. The development of techniques that used in tissue typing laboratory was also developed than previous. All together worked in order to get graft acceptance for long period of time.
Considering the role of HLA matching in transplant outcome. In current years, serological methods have been replaced with DNA based typing methods. The main objective of this study is reviewing the important effect of HLA typing, polymorphism, classification, different techniques used and detecting antibodies against transplanted organ by diverse methods.
- Erlich HA, Opelz G, Hansen J: HLA DNA typing and transplantation. Immunity 2001, 14: 347–356. 10.1016/S1074-7613(01)00115-7View ArticlePubMedGoogle Scholar
- Saiki RK, Bugawan TL, Horn GT, Mullis KB, Erlich HA: Analysis of enzymatically amplified beta-globin and HLA-DQ alpha DNA with allele-specific oligonucleotide probes. Nature 1986, 324: 163–166. 10.1038/324163a0View ArticlePubMedGoogle Scholar
- Anasetti C, Amos D, Beatty PG, Applebaum FR, Bensinger W, Buckner CD, Clift R, Doney K, Martin PJ, Mickelson E, Nisperos B, O'Quigley J, Ramberg R, SandersJ E, Stewart P, Storb R, Sullivan KM, Witherspoon RP, Thomas ED, Hansen JA: Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med 1989, 320: 197–204. 10.1056/NEJM198901263200401View ArticlePubMedGoogle Scholar
- Sheldon S, Poulton K: HLA typing and its influence on organ transplantation. Methods Mol Biol 2006, 333: 157–174.PubMedGoogle Scholar
- Le Bouteiller P, Lenfant F: Antigen-presenting function(s) of the non-classical HLA-E, -F and -G class I molecules: the beginning of a story. Res Immunol 1996, 147: 301–313. 10.1016/0923-2494(96)89643-XView ArticlePubMedGoogle Scholar
- Klein JAN, Sato A: The HLA system: first of two parts. N Engl J Med 2000, 343(10):702–709. 10.1056/NEJM200009073431006View ArticlePubMedGoogle Scholar
- Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Geraghty DE, Hansen JA, Hurley CK, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GM, Strominger JL, Svejgaard A, Terasaki PI, Trowsdale J: Nomenclature for factors of the HLA System, 2004. Tissue Antigens 2005, 65: 301–369. 10.1111/j.1399-0039.2005.00379.xView ArticlePubMedGoogle Scholar
- Marsh SGE, Albert ED, Bodmer WF: Nomenclature for factors of the HLA system, 2010. Tissue Antigens 2010, 75: 291–455. 10.1111/j.1399-0039.2010.01466.xPubMed CentralView ArticlePubMedGoogle Scholar
- Parham P, Ohta T: Population Biology of Antigen Presentation by MHC class I Molecules. Science 1996, 272: 67–74. 10.1126/science.272.5258.67View ArticlePubMedGoogle Scholar
- Robinson J, Waller MJ, Fail SC, McWilliam H, Lopez R, Parham P, Marsh SGE: IMGT/HLA Database. Neucleic Acid Res 2009, 37: 1013–1017. 10.1093/nar/gkn662View ArticleGoogle Scholar
- Rodey GE, Fuller TC: Public epitopes and the antigenic structure of the HLA molecules. Crit Rev Immunol 1987, 7: 229–267.PubMedGoogle Scholar
- Carcia MA, Yebra BG, Flores ALL, Guerra EG: The major histocompatibility complex in transplantation. J Transplan 2012, 20: 842141.Google Scholar
- Pratt JR, Basheer SA, Sacks SH: Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002, 8: 582–587. 10.1038/nm0602-582View ArticlePubMedGoogle Scholar
- Guaní-Guerra E, Santos-Mendoza T, Lugo-Reyes SO, Terán LM: Antimicrobial peptides: general overview and clinical implications in human health and disease. Clin Immunol 2010, 135: 1–11. 10.1016/j.clim.2009.12.004View ArticlePubMedGoogle Scholar
- Opelz G, Mytilineos J, Scherer S: Survival of DNA HLA-DR typed and matched cadaver kidney transplants. Lancet 1991, 338: 461–463. 10.1016/0140-6736(91)90540-6View ArticlePubMedGoogle Scholar
- Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM: Twelve years’ experience with national sharing of HLA-matched cadaveric kidneys for transplantation. N Engl J Med 2000, 343: 1078–1084. 10.1056/NEJM200010123431504View ArticlePubMedGoogle Scholar
- Jung HL: Shedding a new light on the HLA matching. Korean J Hematol 2011, 46: 1–2. 10.5045/kjh.2011.46.1.1PubMed CentralView ArticlePubMedGoogle Scholar
- De Santis D, Dinauer D, Duke J, Erlich HA, Holcomb CL, Lind C, Mackiewicz K, Monos D, Moudgil A, Norman P, Parham P, Sasson A, Allcock RJ: 16(th) IHIW: review of HLA typing by NGS. Int J Immunogenet 2013, 40: 72–76.PubMedGoogle Scholar
- Schiller JJ, Hopp KA, Pietz BC, Bick DP, Lau EC, Ellis TMA: Simplified method for screening siblings for HLA identity using short tandem repeat (STR) polymorphisms. Hum Immunol 2013, 3: 00689. 1 1Google Scholar
- Koclega A, Markiewicz M, Siekiera U, Dobrowolska A, Sylwia M, Dzierzak-Mietla M, Zielinska P, Kruszelnicka MS, Lange A, Kyrcz-Krzemien S: The presence of Anti-HLA antibodies before and after Allogeneic hematopoietic stem cells transplantation from HLA-mismatched unrelated donors. Bone Marrow Res 2012, 24: 539825.Google Scholar
- Warren RP, Storb R, Weiden PL, Su PJ, Thomas ED: Lymphocyte-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity in patients with aplastic anemia: distinguishing transfusion-induced sensitization from possible immune-mediated aplastic anemia. Transplant Proc 1981, 13: 245–247.PubMedGoogle Scholar
- Bodmer JG, Marsh SG, Albert ED, Bodmer WF, Dupont B, Erlich HA, Mach B, Mayr WR: Nomenclature for factors of the HLA system. Hum Immunol 1991, 34: 4–18. 1992 1992View ArticleGoogle Scholar
- Lim SH, Patton WN, Jobson S, Gentle TA, Baynham MID, Franklin IM, Boughton BJ: Mixed lymphocyte reactions do not predict severity of graft versus host disease (GVHD) in HLA-DR compatible, sibling bone marrow transplants. J Clin Pathol 1988, 41: 1155–1157. 10.1136/jcp.41.11.1155PubMed CentralView ArticlePubMedGoogle Scholar
- Dunckley H: HLA typing by SSO and SSP methods. Methods Mol Biol 2012, 882: 9–25. 10.1007/978-1-61779-842-9_2View ArticlePubMedGoogle Scholar
- Adib M, Yaran M, Rezaie A, Solgi GHLA-DR: Typing by polymerase chain reaction with sequence- specific primers compared to serological typing. J Res Med Sci 2004, 6: 255–259.Google Scholar
- Smith LK: HLA typing by direct DNA sequencing. Methods Mol Biol 2012, 882: 67–86. 10.1007/978-1-61779-842-9_5View ArticlePubMedGoogle Scholar
- Qureshi BH: Consensus and controversies on HLA matching and crossmatching in transplantation. Saudi J Kidney Dis Transpl 1997, 8: 138–144.PubMedGoogle Scholar
- Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, Reed EF, Bray RA, Campbell P, Chapman JR, Coates PT, Colvin RB, Cozzi E, Doxiadis II, Fuggle SV, Gill J, Glotz D, Lachmann N, Mohanakumar T, Suciu-Foca N, Sumitran-Holgersson S, Tanabe K, Taylor CJ, Tyan DB, Webster A, Zeevi A, Opelz G: Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013, 15: 19–47.View ArticleGoogle Scholar
- Bray RA, Tarsitani C, Gebel HM, Lee JH: Clinical cytometry and progress in HLA antibody detection. Methods Cell Biol 2011, 103: 285–310.View ArticlePubMedGoogle Scholar
- Gloor J, Stegall MD: Sensitized renal transplant recipients: current protocols and future directions. Nat Rev Nephrol 2010, 6: 297–306.View ArticlePubMedGoogle Scholar
- Minucci PB, Grimaldi V, Casamassimi A: Methodologies for anti-HLA antibody screening in patients awaiting kidney transplant: a comparative study. Exp Clin Transplant 2011, 9: 381–386.PubMedGoogle Scholar
- Süsal C, Opelz G: Impact of HLA matching and HLA antibodies in organ transplantation: a collaborative transplant study view. Methods Mol Biol 2012, 882: 267–277. 10.1007/978-1-61779-842-9_15View ArticlePubMedGoogle Scholar
- Opelz G, Döhler B: Multicenter analysis of kidney preservation. Transplantation 2007, 83: 247–253. 10.1097/01.tp.0000251781.36117.27View ArticlePubMedGoogle Scholar
- Opelz G, Döhler B: Impact of HLA mismatching on incidence of posttransplant non- Hodgkin lymphoma after kidney transplantation. Transplantation 2010, 89: 567–572. 10.1097/TP.0b013e3181c69855View ArticlePubMedGoogle Scholar
- Nikkel LE: Risk of fractures after renal transplantation in the United States. Transplantation 2009, 87: 1846–1851. 10.1097/TP.0b013e3181a6bbdaView ArticlePubMedGoogle Scholar
- Meier-Kriesche HU: A lifetime versus a graft life approach redefines the importance of HLA matching in kidney transplant patients. Transplantation 2009, 88: 23–29. 10.1097/TP.0b013e3181a9ec89View ArticlePubMedGoogle Scholar
- Süsal C, Döhler B, Opelz G: Presensitized kidney graft recipients with HLA class I and II antibodies are at increased risk for graft failure: a collaborative transplant study report. Hum Immunol 2009, 70: 569–573. 10.1016/j.humimm.2009.04.013View ArticlePubMedGoogle Scholar
- El-Awar N: Almost all patients who are waiting for a regraft of a kidney transplanthave anti-HLA antibodies. Transplant Proc 2002, 34: 2531–2532. 10.1016/S0041-1345(02)03520-0View ArticlePubMedGoogle Scholar
- Opelz G, Collaborative Transplant Study: Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 2005, 365: 1570–1576. 10.1016/S0140-6736(05)66458-6View ArticlePubMedGoogle Scholar
- Zou Y: Detection of anti-MICA antibodies in patients awaiting kidney transplantation, during the post-transplant course, and in eluates from rejected kidney allografts byLuminex flow cytometry. Hum Immunol 2006, 67: 230–237. 10.1016/j.humimm.2006.02.017View ArticlePubMedGoogle Scholar
- Reinsmoen NL: Anti-angiotensin type 1 receptor antibodies associated with antibody mediated rejection in donor HLA antibody negative patients. Transplantation 2010, 90: 1473–1477. 10.1097/TP.0b013e3181fd97f1View ArticlePubMedGoogle Scholar
- Morath C: An integrative approach for the transplantation of high-risk sensitized patients. Transplantation 2010, 90: 645–653.View ArticlePubMedGoogle Scholar
- Heinold A, Opelz G, Döhler B, Unterrainer C, Scherer S, Ruhenstroth A, Hien TT: Deleterious impact of HLA-DRB1 allele mismatch in sensitized recipients of kidney retransplants. Transplantation 2013, 15: 137–141.View ArticleGoogle Scholar
- Wang H, He Y, Zhai WJ, Wang M, Zhou Z, Zhao YX, Feng SZ, Han MZ: The impact of recipient HLA-Cw and donor killer immunoglobulin-like receptor genotyping on the outcome of patients receiving HLA-matched sibling donor hematopoietic stem cell transplantation for myeloid malignancies. Swiss Med Wkly 2013, 8: 143. 0 0Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.