• IMMUNE NETWORK
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• 제6권4호
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• pp.179-184
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• 2006

Background: Identification of antigen-specific T cells has yielded valuable information on pathologic process and the disease state. Assays for quantification of inflammatory cytokines or lytic-granule molecules have been generally used to evaluate antigen specific T cell response, however their applicability have been hampered due to the limited source of autologous antigen-presenting target cells (APC). Methods: K562, a leukemic cell line deficient of human leukocyte antigen (HLA), was transfected with a gene encoding HLA-A*02 (K562/ A*02) and its function as stimulator cells in inducing activation of HLA-matched T cells was evaluated by IFN-${\gamma}$ enzyme linked immunospot (ELISPOT) assay. Results: The stable transfectant K562/ A*02 pulsed with HLA- A*02 restricted peptide could specifically induce IFN-${\gamma}$ secretion by CD8+ T cells compared to no detectable secretion by CD4+ T cells. However, CD56+ NK cells secreted IFN-${\gamma}$ in both K562/ A*02 with peptide and without peptide. The number of IFN-${\gamma}$ secreted CD8+ T cells was increased according to the ratio of T cells to K562 and peptide concentration. Formalin-fixed K562/ A*02 showed similar antigen presenting function to live K562/ A*02. Moreover, K562/ A*02 could present antigenicpeptide to not only A*0201 restricted CD8+ T cells but also CD8+ T cells from A*0206 donor. Conclusion: These results suggest that K562/ A*02 could be generally used as target having specificity and negligible background for measuring CD8+ T cell responses and selective use of K562 with responsder matched HLA molecules on its surface as APC may circumvent the limitation of providing HLA-matched autologous target cells.

• IMMUNE NETWORK
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• 제23권6호
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• pp.44.1-44.16
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• 2023

Mesenchymal stem cells (MSCs) are effective in treating autoimmune diseases and managing various conditions, such as engraftment of allogeneic islets. Additionally, autologous and HLA-matched allogeneic MSCs can aid in the engraftment of human allogeneic kidneys with or without low doses of tacrolimus, respectively. However, HLA alloantigens are problematic because cell therapy uses more HLA-mismatched allogeneic cells than autologous for convenience and standardization. In particular, HLA-mismatched MSCs showed increased Ag-specific T/B cells and reduced viability faster than HLA-matched MSCs. In CRISPR/Cas9-based cell therapy, Cas9 induce T cell activation in the recipient's immune system. Interestingly, despite their immunogenicity being limited to the cells with foreign Ags, the accumulation of HLA alloantigen-sensitized T/B cells may lead to allograft rejection, suggesting that alloantigens may have a greater scope of adverse effects than foreign Ags. To avoid alloantigen recognition, the β2-microglobulin knockout (B2MKO) system, eliminating class-I MHC, was able to avoid rejection by alloreactive CD8 T cells compared to controls. Moreover, universal donor cells in which both B2M and Class II MHC transactivator (CIITA) were knocked out was more effective in avoiding immune rejection than single KO. However, B2MKO and CIITA KO system remain to be controlled and validated for adverse effects such as the development of tumorigenicity due to deficient Ag recognition by CD8 T and CD4 T cells, respectively. Overall, better HLA-matching or depletion of HLA alloantigens prior to cell therapy can reduce repetitive transplantation through the long-term survival of allogeneic cell therapy, which may be especially important for patients seeking allogeneic transplantation.

• Clinical and Experimental Pediatrics
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• 제51권1호
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• pp.67-72
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• 2008

목 적 : 본 연구는 HLA가 일치하는 부모로부터 동종조혈모세포이식을 시행받은 소아의 이식 결과를 분석하고자 하였다. 방 법 : 1999년 4월부터 2005년 10월까지 성모병원 조혈모세포이식센터에서 급성 백혈병으로 1차 관해 후 HLA가 일치된 부모로부터 조혈모세포이식을 시행받은 환아 7명(급성 림프모구성백혈병 4명, 급성 골수성백혈병 3명)을 대상으로 하였다. 이식 시 중앙연령은 5세(범위, 1-11세; 남아 2명, 여아 5명), 공여자의 중앙연령은 35세(범위, 30-41세; 남자 5명, 여자 2명)이었다. 이식 후 대상 환아의 생착, 급성이식편대숙주병, 만성이식편대숙주병, 이식관련 사망, 재발, 이식관련 합병증과 생존율 등을 분석하였다. 결 과 : 이식부터 마지막 추적관찰까지 중앙기간이 69.5개월(범위, 18.8-96.5개월)이었다. 이식을 받은 7명의 환아들은 모두 생착이 되었고 호중구와 혈소판의 생착은 이식 후 각각 11일(범위, 10-16일)과 26일(범위, 13-39일)이었다. Grade II의 급성 이식편대숙주병은 3명(43%), grade III의 급성 이식편대숙주병은 1명(14%)에서 발생하였다. 광범위 만성이식편대숙주병은 2명(28%), 제한적 만성이식편대숙주병은 1명(14%)에서 발생하였다. 이식 후 재발은 1명(14%)이었고 이식관련 사망은 1명(14%)이었다. 대상 환아의 이식 후 5년 전체 생존율은 $83{\pm}15%$이었다. 결 론 : 소아 급성 백혈병에서 HLA가 일치하는 부모자식간 동종조혈모세포이식의 결과는 HLA가 일치하는 형제간 조혈모세포이식의 결과와 비견할 수 있으며 동종조혈모세포이식이 필요한 환아에서 형제뿐만이 아니라 부모의 HLA를 검사하면 조혈모세포 공여자 선정의 가능성이 높아진다.

• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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• pp.7007-7010
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• 2013

Background: In the literature, data concerning the relationship between breast cancer and HLA class II gene polymorphisms are limited, so the aim of this study was to determine if HLA-DQB1 and HLA-DRB1 MHC class-II alleles may confer susceptibility or resistance to the disease among Jordanian females. Materials and Methods: This case control study enrolled 56 Royal Hospital breast cancer patients and 60 age matched healthy controls, all of whom provided blood samples (2011-2013). A questionnaire was filled after signing a consent form and DNA was extracted, nucleic acids being amplified for assessment of HLA-DQB1 and HLA-DRB1 alleles by muliplex INNO-LiPA and allele typing carried out by reverse hybridization. Comparison of HLA-DQB1 and HLA-DRB1 allele distributions was carried out with paired t-test and chi-square statistics. Risk factors were assessed by odd ratios with 95% confidence intervals. Results: A significant negative correlation was observed between $HLADQB1^*$ 02 alleles and breast cancers (p=0.013). No significant associations were observed among $HLADQB1^*$ 03, 04, 05 and 06 or among $HLA-DRB1^*$ 01, 03, 04, 07, 08, 10, 11, 13, 14 and 15. Conclusions: $HLADQB1^*$ 02 alleles may provide positive protection against breast tumor risk among Jordanians, but not $HLADQB1^*$ 03, 04, 05 and 06 or $HLA-DRB1^*$ 01, 03, 04, 07, 08, 10, 11, 13, 14 and 15 alleles.

• Asian Pacific Journal of Cancer Prevention
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• 제16권14호
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• pp.6155-6158
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• 2015

Background: The human leukocyte antigen-G (HLA-G) gene is highly expressed in cancer pathologies and is one strategy used by tumor cells to escape immune surveillance. A 14-bp insertion/deletion (InDel) polymorphism of the HLA-G gene has been suggested to be associated with HLA-G mRNA stability and the expression of HLA-G. The aim of present study was to assess any genetic association between this polymorphism and breast cancer among Iranian-Azeri women. Materials and Methods: In this study 227 women affected with breast cancer, in addition to 255 age-sex and ethnically matched healthy individuals as the control group, participated. Genotyping was performed using polymerase chain reaction and electrophoresis assays. The data were compiled according to the genotype and allele frequencies, compared using the Chi-square test. Statistical significance was set at P<0.05. Results: In this case-control study, no significant difference was found between the case and control groups at allelic and genotype levels, although there is a slightly higher allele frequency of HLA-G 14bp deletion in breast cancer affected group. However,when the stage I subgroup was compared with stage II plus stage III subgroup of affected breast cancer, a significant difference was seen with the 14 bp deletion allele frequency. The stage II-III subgroup patients had higher frequency of deletion allele (57.4% vs 45.8%) than stage I cases (${\chi}^2=4.16$, p-value=0.041). Conclusions: Our data support a possible action of HLA-G 14bp InDel polymorphism as a potential genetic risk factor for progression of breast cancer. This finding highlights the necessity of future studies of this gene to establish the exact role of HLA-G in progression steps of breast cancer.

• 대한미생물학회지
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• 제21권2호
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• pp.171-179
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• 1986

The HLA class II region encodes a series of polymorphic glycoproteins that form cell surface heterodimers each consisting of one $\alpha$ and one $\beta$ chain. Thess class II molecules are encoded by genes clustered within three loci. DP, DQ, and DR are functfonally implicated as regulatory signals in intercellular communication during the immune resposes. The phenotypic hallmark of the HLA complex is a high degree of structural and functional polymorphism. Detailed analysis. of such polymorphisms should aid in understanding the molecular basis for associations between HLA and diseases. We have used techniques of restriction enzyme fragment analysis by Southern blotting to investigate polymorphisms associated with DQ $\beta$ class II genes on haplotypes expressing the HLA-DR4 and -DQw3 specificities. The endonucleases Hind III and Bam HI were used to identify a specific DQ $\beta$ genomic polymorphism that precisely corrresponds with the reactivity of a monoclonal antibody A-10-83, previously shown to define a serologic split of DQw3. This study identifies two allelic DQ va. riants. DQw3.1 and DQw3.2. We used these specific genotypic markers to investigate the genomic basis of the association of DR4 with insulin-dependent diabetes mellitus(IDDM) and seropositive juvenile rheumatoid arthritis(JRA). The DR4 positive IDDM demonstrate the predominant expression of DQw3.2 and the very rare expression of DQw3.l. However, in haplotype matched siblings from two IDDM families, all of the DR4 positive siblings display a IDDM-associated DQw3.2 allele. Thus, both affected and healthy individuals can carry the same haplotypes and genomic markers, demonstrating that thess specific allelic variants are genetic elements that indicate a increased risk of IDDM but are not in fact disease specific. We contrasted this result with a similar analysis of patients with another DR4-associated disease, JRA. In contrast to the preponderance of the DQw3.2 allele in IDDM, the JRA patients expressed either the DQw3.1 or the DQw3.2 allele and sometimes both, without apparent association with disease expession. The different genomic markers reported here within HLA-DQ region potentially an analysis of HLA-associated function and disease susceptibility.

• Clinical and Experimental Pediatrics
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• 제46권5호
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• pp.467-473
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• 2003

목 적 : EBV는 전 세계적으로 다양한 질환을 일으키고, EBV는 지역과 EBV에 노출된 사람의 면역 또는 병적 상태에 따라 감염형이 달라 EBV 감염형에 관한 연구는 EBV의 역학연구와 EBV 관련 질환의 병인연구에 제일 기본적이다. EBV의 잠복감염 유전인자들에 의한 세포독성 T 림프구 면역상태는 EBV에 의한 다양한 질환의 병인적 역할이 있으며 HLA에 의하여 유발되어지는 것으로 알려져 있다. 과거에 시행한 많은 연구에서 EBV 감염과 HLA형과의 연관성은 객관적으로 입증되지 않았으나, HLA II형에 속한 항원이 EBV의 인체 내 침투에 관여한다는 사실이 최근에 보고됨으로써 이에 대한 관심이 재조명되고 있다. 이에 저자들은 EBV 감염에 의한 국내 급성 전염성 단핵구증 환아에서 주된 EBV 감염형의 분포를 확인하고, 급성 전염성 단핵구증의 발생이 HLA형과 연관성이 있는 지를 분자생물학적 분류법으로 알아보고자 이 연구를 실시하였다. 방 법 : 연구 대상은 6세에서 13세 사이의 급성 전염성 단핵구증으로 확진된 24명의 환아 이었다. 감염형의 비교 대조군은 건강한 정상 소아 중 면역혈청학적 검사로 EBV 노출이 확인된 동일한 연령의 58명이었고, HLA형 분류의 비교 대조군은 연구대상 환아와 동일한 연령의 정상 소아 200명을 대상으로 실시하였다. EBV에 의한 급성 전염성단핵구증 환아에서 중합 효소 연쇄반응법으로 EBV 감염형을 분류하여 주된 감염형을 확인하고, ARMs PCR법으로 HLA-A, B, C 항원형을, PCR-SSOP법으로 HLA-DRB 항원형을 분류하여 다음과 같은 결과를 얻었다. 결 과 : 1) EBV 감염형 결과 : 연구 대상 환아 24명에서 EBV A형이 20명(83.3%)이었고, B형은 4명(16.7%)이었다. 비교 대조군의 경우에는 58명 중 14명(24.1%)이 EBV가 검출되고 이들 중 A형은 11명(78.6%)이었고, B형이 3명(21.%)이었다. 2) HLA 형 분류 결과 : HLA I형 결과는 HLA-A24형에서 비교 대조군 200명 소아 중 69명이 양성이었고, 연구 대상 환아 24명 중 14명이 양성을 보여 RR치가 3.5724, chi-square치가 5.26, P<0.05으로 통계적 유의성을 보였다. 그러나 HLA-B, C항원형에서는 통계적으로 유의한 결과가 없었다. HLA II형 결과는 HLA-DRB1*07형에서 비교 대조군 200명 소아 중 18명이 양성이었고, 연구 대상 환아 24명 중 8명이 양성을 보여 RR치가 5.6173, chi-square치가 9.73, P<0.01로 통계적 유의성을 보였다. 결 론 : 위의 연구 결과를 통하여 국내 급성 전염성 단핵구증 환아의 EBV 감염형은 정상 비교 대조군의 소아에서 주된 감염형인 A형과 동일한 감염형임을 확인하였다. 그리고 HLA형 연구에서 HLA-A24형과 HLA-DRB1*07형이 정상 대조군과 비교하여 통계적 유의성을 보여 EBV에 의한 급성 전염성단핵구증 발생이 HLA형과 연관성이 있음을 추정하였다.

• Asian Pacific Journal of Cancer Prevention
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• 제17권5호
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• pp.2491-2497
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• 2016

Background: Human leukocyte antigen (HLA) genes have been implicated in cervical cancer in several populations. Objectives: To study the predispositions of HLA alleles/haplotypes with cervical cancer. Materials and Methods: Clinically diagnosed and PAP smear confirmed cervical cancer patients (n 48) and age matched controls (n 47) were genotyped for HLA-A,-B,-DRB1* and DQB1* alleles by PCR-SSP methods. Results: The frequencies of alleles DRB1*04 (OR=2.57), DRB1*15 (OR=2.04), DQB1*0301 (OR=4.91), DQB1*0601 (OR=2.21), B*15 (OR=13.03) and B*07 (OR=6.23) were higher in cervical cancer patients than in the controls. The frequencies of alleles DRB1*10 (OR=0.22) and B*35 (OR=0.19) were decreased. Strong disease associations were observed for haplotypes DRB1*15-DQB1*0601 (OR=6.56; p< $3.5{\times}10^{-4}$), DRB1*14-DQB1*0501 (OR=6.51; p<0.039) and A*11-B*07 (OR=3.95; p<0.005). The reduced frequencies of haplotypes DRB1*10-DQB1*0501 (OR=0.45), A*03-B*35 (OR=0.25) and A*11-B*35 (OR= 0.06) among patients suggested a protective association. HLA-C* typing of 8 patients who possessed a unique three locus haplotype 'A*11-B*07-DRB1*04' (8/48; 16.66%; OR=6.51; p<0.039) revealed the presence of a four locus haplotype 'A*11-B*07-C*01-DRB1*04' in patients (4/8; 50%). Amino acid variation analysis of susceptible allele DQB1*0601 suggested 'tyrosine' at positions ${\beta}9$ and ${\beta}37$ and tyrosine-non-tyrosine genotype combination increased the risk of cervical cancer. Conclusions: Strong susceptible associations were documented for HLA alleles B*15, B*07, DRB1*04, DRB1*15, DQB1*0301, DQB1*0601 and haplotypes DRB1*15-DQB1*0601 and DRB1*14-DQB1*0501. Further, protective associations were evidenced for alleles B*35 and DRB1*10 and haplotypes A*11-B*35 and DRB1*10-DQB1*0501 with cervical cancer in South India.

• Clinical and Experimental Pediatrics
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• 제50권6호
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• pp.519-523
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• 2007

Aplastic anemia is a rare disease, which is characterized by pancytopenia and hypocellular bone marrow without infiltration of abnormal cells or fibrosis. The incidence in Asia is higher than in the West and new cases are diagnosed at a rate of 5.1 per million pediatric populations per year in Korea. The pathophysiology is understood roughly by defective hematopoiesis, impaired bone marrow micro-environment and immune mechanism. Treatments are performed on basis of pathogenesis and selected depending on the severity. Immunosuppressive therapy with antilymphocyte or antithymocyte globulin and cyclosporine is effective in the majority of patients but has some problems including relapse or clonal evolution. Recently, there have been clinical trials of immunosuppression with hematopoietic growth factors or other drugs. Allogeneic hematopoietic stem cell transplantation (HSCT) is curative in children with severe aplastic anemia. The overall survival in HSCT from HLA-identical sibling is higher than alternative donor, including HLA matched unrelated donor or cord blood. We have to consider quality of life after HSCT because of high survival rate. However, chronic graft versus host disease and graft failure are important factors that affect the quality of life and overall survival. We need further investigation to make new regimens aimed at overcoming these risk factors and perform clinical trials.

• Clinical and Experimental Pediatrics
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• 제45권3호
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• pp.370-375
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• 2002

목 적 : 소아의 골수이형성 증후군은 드문 질환군으로 예후가 매우 불량하며 화학요법으로는 완치가 어렵다. 유일한 완치요법으로서 조혈모세포이식이 시행되고 있으나 소아의 경우 증례가 적어 이에 대한 체계적 결과 분석이 빈약한 실정이다. 저자들은 골수이형성증후군에서 조혈모세포이식을 시행한 증례들의 단기간의 결과와 이식합병증들을 분석하고자 하였다. 방 법 : 1995년 11월부터 2001년 1월까지 가톨릭대학교 성모병원 소아과에서 골수이형성 증후군으로 조혈모세포이식을 시행 받은 10명의 환아를 대상으로 하였다. 대상질환은 CMMoL 5례, RAEB 3례, RAEBt 2례이었고, 이식형태는 HLA-일치 형제간 골수이식 4례, 비혈연간 골수이식이 4례, 제대혈 조혈모세포이식이 1례, 가족간 HLA-부분일치 조혈모세포이식이 1례이었다. 전처치로는 BuCy 5례, TBI＋BuCy 2례, BuCy＋ATG, TBI＋Cy 및 TBI＋Melphalan이 각각 1례에서 사용되었다. 결 과 : 1) 10명 모두 생착(100%)되었으며 현재 8명(80%)이 무병생존(3-65개월, 정중 추적기간 11개월) 중이다. 2) 이식전처치로 인한 합병증으로 VOD가 3례에서 관찰되었으나 사망한 예는 없었다. 3) II-III도의 급성 이식편대 숙주병은 5례(50%)에서 발생하였으며 II가 4례, III가 1례이었다. 급성 이식 편대 숙주병과 관련된 사망은 없었다. 4) 전체 환아 10례 중 3례에서 이식 후 재발되었으나 1례는 화학요법 후 조혈모세포구제술에 의하여 현재 무병생존 중이며 2례는 사망하였다. 결 론: 소아 골수이형성 증후군에서 조혈모세포이식은 질환을 완치시킬 수 있는 우수한 결과를 보여주고 있으나 아직 증례가 적고 추적기간이 짧아 향후 더 많은 연구가 필요하다.