Hu-1: Major histocompatibility locus in man

A single locus with 15 or more alleles controls reactivity in mixed leukocyte culture tests. Genes at this locus also control most of the specificities measured by cytotoxic antiserums to leukocytes. Both of these tests can be used to predict survival of skin grafts. It is proposed that this is the major histocompatibility locus in man.     

Relationship of blood type to histocompatibility in chickens

Evidence shows that the B blood group locus in chickens, which controls red cell antigens, is associated with tolerance of skin homografts. Three other blood group loci studied did not show this effect.     

Ranks of donor-recipient histocompatibility for human transplantation

Correlation of leukocyte groups with skin and renal allograft survival indicates that ranks of histocompatibility based upon current genetic concepts of the HL-A system may provide an approach to the selection of optimally compatible subjects for clinical organ transplantation. Such ranks may be expressed as a net histocompatibility ratio (NHR) between prospective donors and recipients. The best clinical results have been when this ratio is of 0.5 to 1. Donor-recipient compatibility situations where the ratio was 0.25 or less have been associated with a high incidence of transplant failure, regardless of whether the organ source was a living, related donor or a cadaver donor.     

Drug-induced tolerance for skin allografts across the H-2 barrier in adult mice

Mice treated with methylhydrazine derivatives for 3 to 4 weeks before the transplantation showed markedly prolonged survival times for allogeneic skin grafts differing at the H-2 histocompatibility locus. Presumably permanent tolerance was induced in about 20 to 30 percent of the mice when the drug treatment was combined with a single injection of additional donor antigen. The tolerance persists without further drug treatment and is specific for donor tissue.     

HOMOGRAFT REJECTION IN THE FETAL LAMB: THE ROLE OF CIRCULATING ANTIBODY

Specific rejection of sterile orthotopic skin homografts by the fetal lamb in utero was unaccompanied by the presence of plasma cells in either the graft and its bed, or in the reactive draining lymph node. The grafts appeared not to stimulate the production of circulating immunoglobulins. The presence in the fetal circulation of rabbit anti-sheep 7S gamma-globulin and anti-beta(2M)-globulin did not inhibit the normal course of homograft rejection. These data support the contention that conventional circulating antibody is not an obligatory participant in the rejection of solid-tissue homografts.     

Essential fatty acid depletion of renal allografts and prevention of rejection

A central hypothesis in transplantation biology is that resident leukocytes expressing class II histocompatibility antigens may determine the immunogenicity of an organ. By means of a novel method to deplete the kidney of resident leukocytes, essential fatty acid deficiency (EFAD), this hypothesis was tested in an intact, vascular organ. Kidneys subjected to EFAD and thus depleted of resident Ia-positive macrophages survived and functioned when transplanted across a major histocompatibility antigen barrier in the absence of immunosuppression of the recipient. Control allografts were rejected promptly. Allografts from donors subjected to EFAD normalized their lipid composition and were repopulated with host macrophages by 5 days. Administration of Ia-positive cells at the time of transplantation established that the resident leukocyte depletion induced by EFAD was responsible for the protective effect. These observations may provide insights into the mechanisms underlying tissue immunogenicity and the population of normal tissues with resident leukocytes.     

Graft versus host inhibition: fetal liver and thymus cells to minimize secondary disease

Long-lived radiation chimeras were produced in mice diflering at the major histocompatibility locus. Survival occurred in lethally irradiated recipients inoculated with allogeneic fetal liver and allogeneic fetal thymus cells in combination. The survival rate was equal or superior to that of mice with transplanted syngeneic fetal, neonatal, or adult hematopoietic cells.     

Genetic control of susceptibility to experimental allergic encephalomyelitis in rats

Rats of the inbred strains Lewis and DA are highly susceptible to the induction of experimental allergic encephalomyelitis (EAE) while Brown Norway rats are resistant to this disease. Evidence has been obtained which suggests that a single dominant gene is associated with susceptibility to EAE. The locus controlling EAE susceptibility is closely linked to the Ag-B histocompatibility locus but is not identical to it.     

Mixed lymphocyte reactions and tissue transplantation tolerance

The induction of tolerance of Lewis histocompatibility antigens in BN rats inoculated at birth with BNI Lewis F(1) hybrid bone marrow cells, as revealed by the prolonged survival of Lewis skin grafts, is accompanied by markedly decreased reactivity in the mixed lymphocyte interaction. Blood lymphocytes from animals inoculated with lymph node cell suspensions also display diminished proliferative reactivity to hybrid BN/Lewis cells in the interaction. However, these recipients are not tolerant of Lewis skin grafts. Blood lymphocytes from BN rats inoculated neonatally with Lewis thymocytes fail to display any level of unresponsiveness in vitro, and such animals are not tolerant of Lewis skin grafts. The results suggest that in rats skin and marrow cells have histocompatibility antigens that are absent or poorly expressed on lymph node cells and thymocytes.     

Serologically defined (SD) locus in cattle

Using cytotoxic serums obtained from multiparous cows or by alloimmunization, we have detected 11 lymphocyte antigens controlled by codominant alleles at a serologically defined locus called BoLA-A (bovine lymphocyte antigens). This locus, along with the lymphocyte defined loci previously reported, establishes the existence of a major histocompatibility system of cattle.     

Homograft tolerance in mice: use of urethan and sublethal irradiation

Adult mice [CBA/J (H-2(k))], which received either a single sublethal dose of x-radiation (500 rad) or urethan plus 500 rad, were given intravenous injections of C3H/HeJ (H-2(k)) spleen or bone marrow cells (18 to 42 x 10(6) cells per mouse) or both, for 3 days. C3H/HeJ tail-skin homografts were retained (over 130 days) by these mice, whereas BALB/cJ (H-2(d)) homografts all were rejected within 33 days. Similarly irradiated or urethan-treated controls (or controls treated with a combination of both), which did not receive C3H cells, rejected both homografts. Specific homograft tolerance is induced in adult mice by this procedure.     

Genetic mapping of Ir locus in man: linkage to second locus of HL-A

Fifty-seven members of a family that spanned three generations were studied for antigen E and ragweed skin sensitivity and HL-A antigens. There was significant association between the haplotype HL-A 2-12 and antigen E skin hypersensitivity (F = .22 to .26) in this family. The map order is first locus of HL-A, second locus of HL-A, and IrE. These determinants are considered to be part of the linkage group HL-1.     

Involvement of a leukocyte adhesion receptor (LFA-1) in HIV-induced syncytium formation

Cell fusion (syncytium formation) is a major cytopathic effect of infection by human immunodeficiency virus (HIV) and may also represent an important mechanism of CD4+ T-cell depletion in individuals infected with HIV. Syncytium formation requires the interaction of CD4 on the surface of uninfected cells with HIV envelope glycoprotein gp120 expressed on HIV-infected cells. However, several observations suggest that molecules other than CD4 play a role in HIV-induced cell fusion. The leukocyte adhesion receptor LFA-1 is involved in a broad range of leukocyte interactions mediated by diverse receptor-ligand systems including CD4-class II major histocompatibility complex (MHC) molecules. Possible mimicry of class II MHC molecules by gp120 in its interaction with CD4 prompted an examination of the role of LFA-1 in HIV-induced cell fusion. A monoclonal antibody against LFA-1 completely inhibited HIV-induced syncytium formation. The antibody did not block binding of gp120 to CD4. This demonstrates that a molecule other than CD4 is also involved in cell fusion mediated by HIV.     

Local recognition of histocompatibility differences in skin grafts

Studies in rabbits of skin grafts tagged with tritiated thymidine indicate a greater proliferation of endothelial cells and fibroblasts at the site of an allograft than at that of an autograft as early as the first day after grafting. It appears, therefore, that allogeneic differences can be recognized and responded to locally almost at once. Labeled nuclear material is found to be transferred from the epithelial cells of skin grafts to host cells of the adjacent tissues. A mechanism therefore exists which might effect a local transfer of information on histocompatibility differences.     

Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice

A polygenic basis for susceptibility to insulin-dependent diabetes in nonobese diabetic (NOD) mice has been established by outcross to a related inbred strain, nonobese normal (NON). Analysis of first and second backcross progeny has shown that at least three recessive genes are required for development of overt diabetes. One, Idd-1s, is tightly linked to the H-2K locus on chromosome 17; another, Idd-2s, is localized proximal to the Thy-1/Alp-1 cluster on chromosome 9. Segregation of a third, Idd-3s, could be shown in a second backcross. Neither Idd-1s nor Idd-2s could individually be identified as the locus controlling insulitis; leukocytic infiltrates in pancreas were common in most asymptomatic BC1 mice. Both F1 and BC1 mice exhibited the unusually high percentage of splenic T lymphocytes characteristic of NOD, suggesting dominant inheritance of this trait. The polygenic control of diabetogenesis in NOD mice, in which a recessive gene linked to the major histocompatibility complex is but one of several controlling loci, suggests that similar polygenic interactions underlie this type of diabetes in humans.     

HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection

Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV.     

鸡Wnt3a的SNPs筛选及其与皮肤毛囊密度性状关联分析

目的 Wnt信号通路在动物皮肤毛囊的发生发育中具有重要作用, 前期研究结果表明Wnt3a可能是影响鸡皮肤毛囊密度性状的重要候选基因。为进一步验证Wnt3a在皮肤毛囊生长发育中的作用, 研究以金陵花鸡为研究对象, 筛选Wnt3a SNPs, 并分析其与毛囊密度性状的相关性, 以期找到对皮肤毛囊密度有显著影响的分子标记, 为培育屠体美观的屠宰型肉鸡的“分子编写育种”提供参考。方法 采用PCR扩增直接测序法对Wnt3a 的SNPs位点进行筛查, 分析单个SNP标记与皮肤毛囊密度性状的相关性。采用Haploview软件分析这些SNP位点的连锁不平衡（LD）程度, 并分析不同单倍型组合与毛囊密度性状的相关性。结果 共发现14个SNP位点, 在第2外显子发现1个SNP位点（SNP1）, 为同义突变;第2内含子发现4个突变位点（ SNP2—SNP5）, 在第3内含子发现9个SNP位点（SNP6—SNP14）。卡方检验表明, 第2外显子的1个突变位点（SNP1）和第2内含子的3个突变位点（SNP3—SNP5）的3个位点均处于哈代-温伯格平衡状态（P>0.05）, 第3内含子的9个SNPs（SNP6-SNP14）偏离哈代-温伯格平衡（P<0.05）。SNP1—SNP5的He均小于0.50, PIC均小于0.25, 这5个SNP位点遗传多样性较低。第3内含子的9个突变位点, SNP6、SNP7、SNP9位点PIC<0.25, 其他6个突变位点 0.25< PIC<0.5, 为中度多态。单标记关联分析表明, 公、母鸡SNP2位点的AG基因型的毛囊密度显著高于GG基因型（P< 0.05）;母鸡SNP8位点的AA与GG基因型的毛囊密度显著高于AG基因型（P < 0.05）, 在公鸡中3种基因型的毛囊密度差异不显著。14个SNPs连锁不平衡分析表明, SNP3、SNP4和SNP5的强连锁产生了2种单倍型, H1（GAT）频率为0.882和H2（TCC）频率为0.118;SNP6—SNP13之间的强连锁产生了5种单倍型, 其中H1（ACATTATC）和H2（ACGTCCCA）, H3（ACGTTCCA）, H4（GTGCTATA）, H5（ACGTCCCC）, 单倍型频率分别为0.469、0.275、0.123、0.113、0.014。SNP3、SNP4和SNP5连锁产生的2 种单倍型组合后产生了3种单倍型组合, 关联分析发现在公、母鸡中3种单倍型组合的毛囊密度均差异不显著;将SNP6—SNP13连锁产生的5种主要单倍型组合后, 公鸡有7种组合单倍型组合, 毛孔数量差异不显著;母鸡有8种主要单倍型组合, 其中H1H1（AACCAATTTTAATTCC）毛囊密度最大。SNP2和SNP8位点与皮肤毛囊密度显著相关, 单倍型组合H1H1（AGAA）、H1H2（AGAG）为母鸡优势单倍型。结论 筛选到Wnt3a的14个SNPs位点, 其中, SNP2（rs2587721 G >A）和SNP8（rs2555967G>A）位点与毛囊密度显著相关, 8个SNPs（SNP6—SNP13）位点处于强连锁不平衡, 母鸡H1H1单倍型毛囊密度最大。Wnt3a的SNP2和SNP8位点的单倍型组合H1H1（AGAA）、H1H2（AGAG）和SNP6—SNP13连锁产生的H1H1（AACCAATTTTAATTCC）单倍型组合与母鸡毛囊密度显著相关, 可以为鸡毛囊密度“分子编写育种”提供重要遗传信息。     

Immunologic inhibition of ultraviolet radiation-induced tumor suppressor cell activity

Long-term exposure of C3H mice to ultraviolet radiation resulted in the formation of suppressor T cells that recognize ultraviolet radiation-induced regressor skin cancers as a class before the appearance of overt tumors. Administration of monoclonal antibodies to the product of the I-Jk subregion of the major histocompatibility complex or low doses of cyclophosphamide in vivo inhibited the development or activity of these cells. This activity of the monoclonal antibody was eliminated by adsorption on B10.BR (I-Jk) but not B10.D2 (I-Jd) splenocytes. These findings provide evidence that elements expressing the I-J determinant are important in regulating the host response prior to the overt development of ultraviolet radiation-induced skin cancers and suggest novel therapeutic approaches to malignancies or other diseases involving suppressor T cells in their pathogenesis.     

Cell mediated immunity: separation of cells involved in recognitive and destructive phases

The mixed leukocyte culture (MLC) and the cell mediated lympholysis (CML) assays are used as in vitro models of the afferent, or recognitive, and efferent, or destructive, phases of the homograft reaction. Activity in both of these tests has been related to differences at the major histocompatibility complex, HL-A in man and H-2 in mouse. Recent evidence suggests that the presumed cell surface differences which lead to cell proliferation in MLC are different from those which act as a target for CML. Data are presented providing further support for this hypothesis; in addition separate cell populations may respond to the differences which activate cells in MLC and to the differences which serve as targets for CML. There thus appears to be a dichotomy both for genetic control of, and cell populations involved in, the recognitive and destructive phases of cell mediated immunity.     

Identification of the miniature pig inbred line by skin allograft

Skin grafting has been used as one of the most reliable tests to determine the genetic stability of laboratory animal such as mice and rats inbred line, but no identification of swine inbred lines by skin grafting has been reported. At present, Wuzhishan miniature pig(WZSP) inbred line has acquired the F24 individuals in China. In order to verify whether WZSP inbred line had been cultivated successfully, allogeneic skin grafts and related research were performed on F20 individuals of WZSP inbreeding population, compared with a control group of autologous transplantation. We observed the transplant recipients' wounds, detected peripheral blood-related indicators interleukin-2, 4 and 10, CD4+ and CD8+ lymphocytes, and conducted hematoxylin-eosin(HE) and Masson's staining of skin to judge whether the immune rejection reactions occurred within 28 days after transplantation. Chr. 7 genomic heterozygosity of 48 WZSP individuals from F20 to F22 was analyzed by high-density single nucleotide polymorphism(SNP) chips(60 000 SNPs). The result showed that there were no significant differences in graft skin, the plasma interleukin-2, 4, 10, CD4+ and CD8+, HE and Masson's staining results between the allograft and autograft groups, and no immune rejection occurred on the allograft group. We found that 11 genes in Chr. 7 of major histocompatibility complex(MHC) I and MHC II were homozygous which confirmed that immune antibody of the allograft and autograft groups were highly identical and also provided a theoretical basis to no immune rejection occurred on the allograft in the inbred WZSP. The result proved that the WZSP inbred line had been cultivated successfully for the first time in the world. The test methods also provide a scientific basis for the identification of swine and mammal inbred lines.