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© Borgis - Postępy Nauk Medycznych 7/2011, s. 553-559
*Monika Dzierżak-Mietła1, Mirosław Markiewicz1, Urszula Siekiera2, Sławomira Kyrcz-Krzemień1
Występowanie niezgodności słabych antygenów zgodności tkankowej w allogenicznych przeszczepieniach komórek krwiotwórczych od zgodnego w układzie HLA rodzeństwa
Occurrence of minor histocompatibility antigens’ disparities in allogeneic hematopoietic stem cell transplantation recipients and their HLA-matched siblings
1Hematology and Bone Marrow Department, Medical University of Silesia, Katowice
Head: prof. Sławomira Kyrcz-Krzemień
2Immunogenetics and HLA Laboratory, Regional Blood Center, Katowice
Head: dr Stanisław Dyląg
Oznaczyliśmy allele jedenastu słabych antygenów zgodności tkankowej (mHAg) i zbadaliśmy występowanie ich immunogennych niezgodności pomiędzy dawcą i biorcą w 35 allogenicznych przeszczepieniach komórek krwiotwórczych od zgodnego w układzie HLA rodzeństwa wykonanych z zastosowaniem przygotowania mieloablacyjnego w latach 2000-2008. Niezgodności były ukierunkowane w stronę przeszczep-przeciw gospodarzowi (GVH) lub gospodarz-przeciw przeszczepowi (HVG). Analiza częstości występowania alleli, genotypów i fenotypów, uwzględniająca występowanie odpowiednich antygenów restrykcyjnych HLA pozwoliła na oszacowanie prawdopodobieństwa wystąpienia immunogennej niezgodności. Następnym etapem pracy będzie zbadanie związku pomiędzy wykrytymi niezgodnościami mHAg pomiędzy dawcą i biorcą a przebiegiem klinicznym procedury przeszczepowej.
We have determined the alleles of eleven minor histocompatibility antigens (mHAgs) and investigated the occurrence of immunogenic mHAgs mismatches between a donor and a recipient of allogeneic hematopoietic stem cell transplantation (alloHSCT) from HLA-matched sibling donors in 35 recipients after myeloablative conditioning between 2000 and 2008. Mismatches were either graft-versus-host or host-versus-graft directed. The frequency analysis of mHAg alleles, genotypes and phenotypes accompanied by appropriate restriction HLA antigens allowed for estimation of the probability of immunogenic mismatches. The investigation of the association of detected immunogenic mHAgs mismatches between a donor and a recipient with a course of alloHSCT is warranted.

The allogeneic hematopoietic stem cell transplantation (alloHSCT) constitutes a recommended therapy of many proliferative, especially hemato-oncologic diseases. Despite the fact, that hematopoietic stem cell transplantology develops very dynamically, and almost 40 years have passed since the first alloHSCT, early and late complications of post-transplant care remain unresolved. Early complications include conditioning toxicity (nausea, vomitus, alopecia, hemorrhagic cystitis, sinusoidal obstruction syndrome, interstitial pneumonia, thrombotic microangiopathy), pancytopenia with related infections and acute graft-versus-host disease (a-GVHD). Late complications include those related to conditioning toxicity (infertility, cataract, hypothyreosis, secondary malignancies) and chronic graft-versus-host disease (cGVHD).
Although the prognosis after alloHSCT depends mainly of the disease, long survival is being estimated in the range of 40-70%. Infectious complications and GVHD (30-40%), organ toxicity of chemotherapy (20%) and relapse (20-30%) are the most frequent causes of failures.
The possession of a HLA-matched donor is a key requirement for alloHSCT therapy. Tissue histocompatibility is determined by genes of major histocompatibility complex (MHC), which in man is known as a HLA (human leukocyte antigens). The genes encoding HLA antigens system are located in the short arm of chromosome 6. The products of the HLA genes can be divided into class I (HLA-A,-B,-C) and class II (HLA-DP,-DQ,-DR) molecules. Class I HLA antigens are expressed on most of nucleated cells, excluding red blood cells and cells of the nervous system, while class II HLA molecules occur mainly on B cells, macrophages, dendritic cells and thymic epithelial cells. Molecules of both classes differ in structure, tissue distribution and characteristics of peptide presentation to T-lymphocytes which plays a major role in creating immunity. HLA typing- key element of donor-recipient pair matching- is managed with use of serological and more accurate bio-molecular methods based on identification of HLA-antigens encoding DNA.
The DNA typing methods include:
a) specific sequences of DNA nucleotides (SSOP – sequence-specific oligonucleotide probe),
b) DNA sequence-specific primers (SSP – sequence specific primers),
c) direct nucleotide sequencing (SBT – sequence based typing),
d) other methods such as using a hetero-duplex analysis.
Matching of HLA compatible donor is the most important single factor determining the outcome of allogeneic transplantation, affecting the possible loss of graft, the incidence and severity of GVHD and survival.
Siblings are the first to be tested in order to find an optimal donor of hematopoietic cells. The odds ratio for HLA compatibility in siblings is 1:4. The probability of having a compatible donor among siblings by a particular patient is determined by the formula 1- (0.75)n, where n is the number of possessed siblings. In case of the absence of siblings or lack of compliance, search of an unrelated donor is performed. When not successful, it is followed by an alternative donor search, i.e. an unrelated HLA mismatched, or donor from extended family.
The probability of finding an unrelated donor is dependent upon the prevalence of certain haplotypes in the general population. Odds ratio of finding an unrelated donor is about 1:10 000, but in case of a search of world registers which contain search determinants currently of more than 15 million donors, it is possible to find one for the majority of patients in need.
Unfortunately, failure of treatment is observed in some patients despite full HLA-match of donor-recipient pair, a state of disease remission before transplantation and the best course of transplant procedure. Excluding the possibility of incorrect HLA typing it can be suspected, that mismatched minor histocompatibility antigens (mHAgs) may be responsible. These antigens belong to a very heterogeneous group of peptides, usually composed of 9-12 amino-acids. Disparities in the mHAgs result from polymorphism of amino-acids which they are composed of, as a consequence of polymorphisms of genes encoding them. The product of each polymorphic gene in combination with molecules of the major histocompatibility complex MHC may induce a response and act as a transplant mHAg. mHAg are encoded by autosomal genes or gender genes located on the Y chromosome, which thus do not occur in women. Most of mHAgs are encoded by one immunogenic and one non-immunogenic allele, and in fact one allele determines the potential strength of their immunogenicity. mHAgs are being presented after binding to the appropriate binding site of the HLA class I or class II molecule. The dependence of mHAgs immunogenicity from the presence of specific HLA molecule possessing an adequate peptide binding site specific for each particular mHAg is called MHC restriction. Autosomal and Y-chromosome encoded mHAgs are presented in Tables 1 and 2, respectively.
Table 1. mHAg autosomal encoded.
mHAgRestrictionIdentificationClinical trialsProteinTissue distribution
HA-1HLA-A*02Den Haan 1998Goulmy 1996
Tseng 1999
Gallardo 2001
HA-1RestrictedHematopoietic cells
Bronchial Carcinomas
Cervix Carcinoma
Breast Carcinoma
Prostate Carcinoma
HA-1/B60HLA-B*60Mommaas 2002-HA-1RestrictedHematopoietic cells
HA-2HLA-A*02Den Haan 1995Goulmy 1996Myosin 1GRestrictedHematopoietic cells
HA-3HLA-A*01Spierings 2003Goulmy 1996Lymphoid blast crisis oncogeneBroadHematopoietic cells
HA-8HLA-A*02Brickner 2001Akatsuka 2003
Perez-Garcia 2005
KIAA0020BroadHematopoietic cells
HB-1H/YHLA-B*44Dolstra 1999-unknownRestrictedB cell ALL, EBV-BLCLs
ACC-1HLA-A*24Akatsuka 2003Nishida 2004BCL2A1RestrictedHematopoietic cells
ACC-2HLA-B*44Akatsuka 2003-BCL2A1RestrictedHematopoietic cells
SP110 (HwA-9)HLA-A*03Warren 2006-SP110 intranuclear proteinRestrictedHematopietic cells
IFN– gamma inducible
PANE1 (HwA-10)HLA-A*03Brickner 2006-PANE1RestrictedLymphoid cells
UGT2B17/A29HLA-A*29Murata 2003-UGT2B17RestrictedDendritic cells, B- cells, EBV-BLCLs
UGT2B17/B44HLA-B*44Terrakura 2007UGT2B17RestrictedDendritic cells, B- cells, EBV-BLCLs
LRH-1HLA-B*07de Rijke 2005-P2X5RestrictedT cells, B cells, NK cells, PHA blasts, EBV-BLCLs, AML
LB-ECGF-1HHLA-B*07Slager 2006-ECGF-1RestrictedHematopoietic cells
CTSH/A31HLA-A*31Torikai 2006-Cathepsin HRestrictedEBV-BLCLs, AML
CTSH/A33HLA-A*33Torikai 2006-Cathepsin HRestrictedEBV-BLCLs, AML
LB-ADIR-1FHLA-A*02van Bergen 2007-TOR3ARestricted-
ACC-6HLA-B*44Kawase 2007-HMSDRestricted-
Table 2. mHAg encoded by the Y chromosome.
mHAgRestrictionIdentificationClinical trialsProteinTissue distribution
A1/HYHLA-A*01Pierce 1999-USP9YBroadHematopoietic cells, fibroblasts
A2/HYHLA-A*02Meadows 1997Goulmy 1996SMCYBroadHematopoietic cells, fibroblasts
A33/HYHLA-A*33Torikai 2004-TMSB4YBroadHematopoietic cells
B7/HYHLA-B*07Wang 1995-SMCYBroadHematopoietic cells
B8/HYHLA-B*08Warren 2000-UTYRestrictedHematopoietic cells
B52/HYHLA-B*52Ivanov 2005-RPS4Y1RestrictedLeukocytes, PHA blasts, EBV-BLCLs, B cells, Breast carcinoma, Hepatocellular carcinoma, Colon adenocarcinoma, AML, ALL Multiple myeloma
B60/HYHLA-B*60Vogt 2000-UTYBroadHematopoietic cells, fibroblasts
DRB1*1501/HYHLA-DRB1*15Zorn 2004-DDX3Y (DBY)BroadHematopoietic cells, fibroblasts
DRB3*0301/HYHLA-DRB3*0301Spierings 2003-RPS4Y1BroadHematopoietic cells, fibroblasts
DQ5/HYHLA-DQB1*05Vogt 2002-DDX3Y (DBY)BroadHematopoietic cells, Fibroblasts
Abbreviations: HUVE – human umbilical vein epithelium, PTE – proximal tubular epithelium, EBV-BLCL – Epstein Barr virus transformed B – lymphoblastoid cell lines, PHA – phytohaemagglutynin
Data in table 1 and 2 are based on materials presented during „Minor histocompatibility workshop” 2005, Leiden Univeristy Medical Center; Eric Spierings: Minor H antigens: targets for tumour therapy – lecture at the conference, „Immunogenetics in haematology and stem cell transplantation”, Wrocław 09.02.2006; and Spierings E., Goulmy E.: Expanding the immunotherapeutic potential of minor histocompatibility antigens. J Clin Invest 2005, 115, 3397-3400.

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otrzymano: 2011-05-04
zaakceptowano do druku: 2011-06-09

Adres do korespondencji:
*Monika Dzierżak-Mietła
Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia
Dabrowskiego 25 Street, Katowice 40-032
phone: +48 (32) 256-28-58, fax: +48 (32) 255-49-85
e-mail: klinhem@sum.edu.pl

Postępy Nauk Medycznych 7/2011
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