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PubMed1997

The red deer (Cervus elaphus) contains two expressed major histocompatibility complex class II DQB genes.

The highly variable second exons of the red deer (Cervus elaphus) major histocompatibility complex (MHC) DQB genes were cloned and sequenced. Eight different expressed DQB sequences were isolated from four unrelated red deer. Either two or three different DQB sequences were isolated from each individual, demonstrating that more than one DQB gene is expressed in red deer. This is consistent with other ruminant, which also have multiple expressed copies of the DQB gene. The sequences ranged in similarity from 81.3% to 97.6% with an average similarity of 90.2%; this indicates that at least one of the DQB genes is highly polymorphic.

Amino Acid Sequence↗
PubMed1997

Canine major histocompatibility complex genes DQA and DQB in Irish setter dogs.

Information about genetic variation within the canine major histocompatibility complex (MHC) class II genes is limited. In common with most other vertebrate species the canine MHC, or DLA, includes genes which are homologous to human DR, DQ, and DP. Recently, at least one functional DLA DQ gene-pair has been characterized, but so far systematic screening efforts have been lacking. In the present study, we sequenced both cDNA and genomic clones derived from DLA DQ genes of Irish setter dogs. This breed was of interest, since it shows a high prevalence of gluten sensitive enteropathy (GSE), which may be a useful animal model for celiac disease (CD) of man. Interestingly, few of the alleles found in Irish setters were identical to those previously detected in other breeds. Three novel DLA DQA and four novel DLA DQB alleles were discovered in 19 unrelated dogs. Strong association between certain HLA DQ alleles and CD of man prompted us to screen the DQ alleles of members of a family of gluten-sensitive Irish setter dogs. No haplotypes or alleles were shared by all affected dogs, but one frequent haplotype in this family was also detected in an unrelated gluten-sensitive Irish setter; this haplotype was absent in the healthy dogs. This observation warrants further investigation by screening the DQ alleles of a large population of unrelated gluten-sensitive Irish setters.

Alleles↗
PubMed2006

The association between non-melanoma skin cancer and a young dimorphic Alu element within the major histocompatibility complex class I genomic region.

A non-melanoma skin cancer (NMSC) susceptibility locus within the major histocompatibility complex (MHC) class I region was previously identified telomeric of the HLA-C gene using high-density microsatellite markers. Here, we have extended the previous microsatellite study by using the same DNA samples obtained from 154 NMSC patients and 213 normal controls from the town of Busselton in Western Australia and examined the relationship between five polymorphic Alu insertions (POALINs) within the MHC class I region and their association with NMSC. The genotype distribution of the AluyTF insertion that is located within the NMSC susceptibility region telomeric of the HLA-C gene was significantly increased according to the Fisher's exact test in the NMSC patients, and it was not in Hardy-Weinberg equilibrium in the control group. There was no difference between the cancer patients and controls for the genotypes of the AluyMICB locus within intron 1 of the MICB gene and the other three POALINs (AluyHJ, AluyHG and AluyHF) that are located within the genomic region of the HLA-A, -G and -F gene cluster. The test for significant linkage disequilibrium for 10 pairs of POALIN loci and estimations of two locus POALIN haplotype frequencies also revealed AluyTF differences between the cases and controls. In conclusion, the MHC class I POALIN, AluyTF, that is located within the NMSC susceptibility locus and near the HLA-C gene was strongly associated with NMSC. This finding, using five different polymorphic Alu insertion markers, supports the previous microsatellite association study that one or more genes located in close proximity to the AluyTF insertion has a potential role in NMSC.

Aged↗
PubMed1998

Regulation of major histocompatibility complex and TAP gene products in preimplantation mouse stage embryos.

PROBLEM: To determine the ontogeny of major histocompatibility complex (MHC) expression and TAP products in mouse embryos. METHOD OF STUDY: mRNAs encoding MHC and associated molecules were identified by reverse transcriptase-polymerase chain reaction, and the protein products were localized by confocal microscopy. RESULTS: mRNAs encoding class Ia (H-2Db) and class Ib (Q7/9) were present in one-cell embryos, whereas beta 2-microglobulin (beta 2-m) transcripts were not detected until the two-cell stage. Transporter TAP1, but not TAP2, transcripts were detected only in blastocysts. H-2 class Ia (classical) protein was detected on the surface of two-cell embryos, H-2 class Ib (nonclassical) protein was detected on one-cell embryos, and beta 2-m transcripts were detected on eight-cell embryos; TAP1 protein was present at low levels in the cytoplasm from the one-cell stage onward, increasing in expression in blastocysts. CONCLUSIONS: In mice, MHC class I mRNAs encoding the heavy chain of H-2- and Q7/9-encoding Qa2 molecules are synthesized soon after conception prior to implantation. Similarly, the nonpolymorphic MHC class I-associated molecule beta 2-m also is expressed before implantation. TAP1, but not TAP2, is first detected at the blastocyst stage, thus preceding the onset of TAP2 in embryonic development.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Theiler's virus persistence and demyelination in major histocompatibility complex class II-deficient mice.

Mice with targeted disruption of the A beta gene of major histocompatibility complex class II molecules (Abo) were used to investigate the role of class II gene products in resistance or susceptibility to virus-induced chronic demyelination in the central nervous system (CNS). Class-II-deficient mice from the resistant H-2b [H-2b(Abo)] and nonmutant H-2b backgrounds were infected with Theiler's murine encephalomyelitis virus intracerebrally and examined for CNS virus persistence, demyelination, and neurologic clinical signs. Virus titers measured by plaque assays showed that 8 of 10 normally resistant nonmutant H-2b mice had cleared the virus within 21 days, whereas the other 2 mice had low titers. In contrast, all class II-deficient Abo mice had high virus titers for up to 90 days after infection (4.30 log10 PFU per g of CNS tissue). Virus antigens and RNA were localized to the brains (cortex, hippocampus, thalamus, and brain stem) and spinal cords of Abo mice. Colocalization identified persistent Theiler's murine encephalomyelitis virus in oligodendrocytes and astrocytes but not in macrophages. There was demyelination in 11 of 23 and 6 of 9 Abo mice 45 and 90 days after virus infection, respectively, whereas no demyelination was observed in infected nonmutant H-2b mice. Demyelinating lesions in Abo mice showed virus-specific CD8+ T cells and macrophages but no CD4+ T cells. Spasticity and paralysis were observed in chronically infected Abo mice but not in the nonmutant H-2b mice. These findings demonstrate that class II gene products are required for virus clearance from the CNS but not for demyelination and neurologic disease.

Animals↗
PubMed2003

Histone deacetylase 1/mSin3A disrupts gamma interferon-induced CIITA function and major histocompatibility complex class II enhanceosome formation.

The class II transactivator (CIITA) is a master transcriptional regulator of major histocompatibility complex class II (MHC-II) promoters. CIITA does not bind DNA, but it interacts with the transcription factors RFX5, NF-Y, and CREB and associated chromatin-modifying enzymes to form an enhanceosome. This report examines the effects of histone deacetylases 1 and 2 (HDAC1/HDAC2) on MHC-II gene induction by gamma interferon (IFN-gamma) and CIITA. The results show that an inhibitor of HDACs, trichostatin A, enhances IFN-gamma-induced MHC-II expression, while HDAC1/HDAC2 inhibits IFN-gamma- and CIITA-induced MHC-II gene expression. mSin3A, a corepressor of HDAC1/HDAC2, is important for this inhibition, while NcoR, a corepressor of HDAC3, is not. The effect of this inhibition is directed at CIITA, since HDAC1/HDAC2 reduces transactivation by a GAL4-CIITA fusion protein. CIITA binds to overexpressed and endogenous HDAC1, suggesting that HDAC and CIITA may affect each other by direct or indirect association. Inhibition of HDAC activity dramatically increases the association of NF-YB and RFX5 with CIITA, the assembly of CIITA, NF-YB, and RFX5 enhanceosome, and the extent of H3 acetylation at the MHC-II promoter. These results suggest a model where HDAC1/HDAC2 affect the function of CIITA through a disruption of MHC-II enhanceosome and relevant coactivator-transcription factor association and provide evidence that CIITA may act as a molecular switch to modulate MHC-II transcription by coordinating the functions of both histone acetylases and HDACs.

Acetylation↗
PubMed1992

Effect on insulin production sorting and secretion by major histocompatibility complex class II gene expression in the pancreatic beta-cell of transgenic mice.

Expression of major histocompatibility complex (MHC) class II protein in islet beta-cells of transgenic mice causes severe diabetes without an attendant autoimmune component. Little is known of the aberrant beta-cell function and site of biological lesions responsible for the diabetic state. Therefore, changes in (pro)insulin production, processing, sorting, storage, and secretion were evaluated using the in vitro perfused pancreas from male hyperglycemic BALB/cBYJ Tg (O pinsproA alpha d pinsproA beta d) mice and a RIA capable of detecting mouse insulin or proinsulin with quantitative equivalency. Results were compared to control pancreases from normal BALB/cBYJ mice. Extractable pancreatic insulin plus proinsulin content in the transgenics was 4% of normal. Normal pancreases responded characteristically with a diphasic insulin release during 30-min stimulation by glucose, a response that was enhanced by subsequent forskolin. In contrast, hormone release from transgenic pancreases was undetectable; based on the sensitivity of the immunoassay, fractional secretion of the residual pancreatic hormone content from the transgenic pancreases was less than 25% of normal. Proinsulin or insulin constitutive release was also not detected in the absence or presence of glucose-containing stimuli even when experiments were extended to 3 h. In contrast, fractional secretion in response to nonglucose stimuli (carbachol-leucine and arginine-leucine) was greater than normal from the transgenic diabetic pancreases. Responses to glucose stimuli did not normalize even after 90 min in the absence of glucose. In other experiments, pancreases were stimulated with carbachol/leucine/forskolin for 90 min, and the proportion of proinsulin to insulin released by the regulated pathway was determined after Sep-Pak and HPLC separation of combined eluates. Proinsulin was undetectable (and, therefore, accounted for less than 10% of the total hormone secretion). It is concluded from the observations of hyperglycemia, low pancreatic insulin content, and impaired release that insulin production in the pancreas of the MHC diabetic transgenic is severely depressed. The limited insulin production and chronic hyperglycemia do not (as speculated) cause missorting to a constitutive pathway or impaired conversion of proinsulin to insulin, since a proportionately increased proinsulin release does not occur. Although the response of the secretory process to glucose-containing stimuli is almost completely destroyed, fractional secretion in response to nonglucose stimuli is enhanced. The possible contribution of hyperglycemia-induced beta-cell desensitization or specific lesions in the glucose recognition signals induced by MHC expression are discussed. Results suggest that expression of MHC class II protein causes highly specific beta-cell lesions which, in themselves, could be a contributing factor in human insulin-dependent diabetes.

Animals↗
PubMed1997

Effect of interferon-gamma and glucose on major histocompatibility complex class I and class II expression by pancreatic beta- and non-beta-cells.

Surface major histocompatibility complex (MHC) class I and class II expression by pancreatic islet cells is considered a local initiator or regulator of immune processes that can lead to diabetes. Locally released cytokines, in particular interferon-gamma, are known to stimulate MHC antigen expression by islet cells. The present study quantifies MHC expression in cultured pancreatic beta- and non-beta-cells from both rat and human organs. Interferon-gamma increased MHC class I expression in endocrine beta- and non-beta-cells as well as in pancreatic ductal cells. The cytokine induced a 6-fold increase in the MHC class I messenger ribonucleic acid levels in pancreatic beta-cells; this effect was 2-fold amplified in the presence of elevated glucose levels (20 mmol/L instead of 6 mmol/L). No MHC class II expression was observed in endocrine beta- or non-beta-cells; human, but not rat, ductal cells exhibited MHC class II expression that increased in the presence of interferon-gamma. These data indicate that the increase in beta-cell MHC class I expression described in the pancreata of diabetic patients may result from stimulated transcription after exposure to locally released interferon-gamma and/or to a hyperglycemic state. The association of human islets with ductal cells in which MHC class II expression is stimulated by interferon-gamma makes these cells potential participants in the autoimmune process in diabetes.

Adolescent↗
PubMed1997

Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex.

Major histocompatibility complex (MHC) class II antigens are expressed on adrenocortical cells of the zona reticularis and have been shown to be a marker of dignity. This suggests a correlation to the zellular differentiation of the adrenal cortex. Therefore, we immunohistochemically investigated the MHC class II expression in the context of the ontogenesis of the zonal and cellular differentiation in fetal, postnatal, childhood, and adult adrenals. Cell types and cell turnover were studied using specific immune markers (including expression of CD95/ Fas), in situ end labeling of apoptosis, and electron microscopy. We show that prenatal (fetal and definitive) steroid cells, as well as postnatal adrenals, reveal no expression of MHC class II. In childhood, these antigens first appear by the fourth year, in parallel with the differentiation of reticularis cells. The expression index in childhood was 7.43% +/- 2.78 (mean +/- SEM), in adult adrenals 18.63% +/- 3.14 (third decade), and 15.15% +/- 1.26 (fourth through sixth decade). In conclusion, MHC class II expression and the development of the functional maturation of the adult adrenal cortex occur simultaneously. The expression of MHC class II on steroid cells may thus be involved in potential immune-adrenal interactions.

Adrenal Cortex↗
PubMed2004

17beta-Estradiol inhibits class II major histocompatibility complex (MHC) expression: influence on histone modifications and cbp recruitment to the class II MHC promoter.

Major histocompatibility complex (MHC) class II proteins are important for the initiation of immune responses and are essential for specific recognition of foreign antigens by the immune system. Regulation of class II MHC expression primarily occurs at the transcriptional level. The class II transactivator protein is the master regulator that is essential for both constitutive and interferon-gamma-inducible class II MHC expression. Estrogen [17beta-estradiol (17beta-E2)] has been shown to have immunomodulatory effects. In this study, we show that 17beta-E2 down-regulates interferon-gamma inducible class II MHC protein levels on brain endothelial cells, as well as other cell types (astrocytes, fibrosacroma cells, macrophages). The inhibitory effects of 17beta-E2 on class II MHC expression are not due to changes in class II transactivator mRNA or protein levels, rather, 17beta-E2 mediates inhibition at the level of class II MHC gene expression. We demonstrate that 17beta-E2 attenuates H3 and H4 histone acetylation and cAMP response element binding protein-binding protein association with the class II MHC promoter, suggesting that 17beta-E2 inhibits class II MHC expression by a novel mechanism involving modification of the histone acetylation status of the class II MHC promoter.

Acetylation↗
PubMed2006

Transcriptional regulation of major histocompatibility complex class I gene by insulin and IGF-I in FRTL-5 thyroid cells.

Increased major histocompatibility complex (MHC) class I gene expression in nonimmune cell 'target tissues' involved in organ-specific diseases may be important in the pathogenesis of autoimmune diseases. This possibility in part evolves from studies of cultured thyrocytes where properties appear relevant to the development of thyroid autoimmune disease. In FRTL-5 rat thyroid cells in continuous culture, hormones and growth factors that regulate cell growth and function specifically decrease MHC class I gene expression. We hypothesized that this could reflect a mechanism to preserve self-tolerance and prevent autoimmune disease. The mechanisms of action of some of these hormones, namely TSH and hydrocortisone, have been already characterized. In this report, we show that IGF-I transcriptionally downregulates MHC class I gene expression and that its action is similar to that of insulin. The two hormones have a complex effect on the promoter of the MHC class I gene, PD1. In fact, they decrease the full promoter activity, but upregulate the activity of deleted mutants that have lost an upstream, tissue-specific regulatory region but still retain the enhancer A region. We show that insulin/IGF-I promotes the interactions of the p50/p65 subunits of NF-kappaB and AP-1 family members with these two regions, and that the tissue-specific region acts as a dominant silencer element on insulin/IGF-I regulation of promoter activity. These observations may be important to understand how MHC class I gene transcription is regulated in the cells.

Animals↗
PubMed2002

Effects of major histocompatibility complex class II knockout on mouse bone mechanical properties during development.

We investigated the effect of major histocompatibility complex class II (MHC II) knockout on the development of the mouse peripheral skeleton. These C2D mice had less skeletal development at 8, 12 and 16 weeks of age compared to wild-type C57BL/6J (B6) male mice. The C2D mice had decreased femur mechanical, geometric and compositional measurements compared to wild type mice at each of these ages. C2D femur stiffness (S), peak force in 3-pt bending (Pm), and mineral mass (Min-M) were 74%, 64% and 66%, respectively, of corresponding B6 values at 8 weeks of age. Similar differences were measured at 12 weeks (for which C2D femoral S, Pm and Min-M were 71%, 72% and 73%, respectively, of corresponding B6 values) and at 16 weeks (for which C2D femoral S, Pm and Min-M were 80%, 66% and 61%, respectively, of corresponding B6 values). MHC II knockout delays the development of adult bone properties and is accompanied by lower body mass compared to wild-type controls.

Animals↗
PubMed2006

First report of major histocompatibility complex class II loci from the Amazon pink river dolphin (genus Inia).

We report the first major histocompatibility complex (MHC) DQB1 sequences for the two species of pink river dolphins (Inia geoffrensis and Inia boliviensis) inhabiting the Amazon and Orinoco River basins. These sequences were found to be polymorphic within the Inia genus and showed shared homology with cetacean DQB-1 sequences, especially, those of the Monodontidae and Phocoenidae. On the other hand, these sequences were shown to be divergent from those described for other riverine dolphin species, such as Lipotes vexillifer, the Chinese river dolphin. Two main conclusions can be drawn from our results: 1) the Mhc DQB1 sequences seem to evolve more rapidly than other nuclear sequences in cetaceans, and 2) differential positive selective pressures acting on these genes cause concomitant divergent evolutionary histories that derive phylogenetic reconstructions that could be inconsistent with widely accepted intertaxa evolutionary relationships elucidated with other molecular markers subjected to a neutral dynamics.

Amino Acid Sequence↗
PubMed1991

Heterogeneous induction of major histocompatibility complex class II antigens on corneal endothelium by interferon-gamma.

The expression and distribution of major histocompatibility complex (MHC) class II gene products, HLA-DR, HLA-DQ, and the HLA-DR invariant chain, were studied on flat mounts of human corneal endothelial cells (HCEC) after in vitro incubation of donor corneas with interferon-gamma (IFN-gamma), interleukin-1 (IL-1), and IL-6, using a sensitive immunoperoxidase technique with monoclonal antibodies. Control HCEC and endothelium treated with IL-1 or IL-6 completely lacked MHC class II antigens. After treatment with 50 U/ml, 100 U/ml, 500 U/ml, and 5000 U/ml of human IFN-gamma, a mosaic-like, patchy staining for all MHC class II products was observed: part of the HCEC showed membranous and/or cytoplasmic positivity; other endothelial cells were negative. In addition, a dose-dependent response to IFN-gamma was observed: the proportion of cells expressing class II products rose with increasing doses of IFN-gamma. The induction of MHC class II antigen expression on HCEC by IFN-gamma was completely inhibited by the addition of a neutralizing antibody directed to IFN-gamma but not by IL-1 beta. The significance of these findings with respect to corneal transplantation immunology is discussed.

Antibodies, Monoclonal↗
PubMed1985

The role of T8 in the cytotoxic activity of cloned cytotoxic T lymphocyte lines specific for class II and class I major histocompatibility complex antigens.

It is reported here that most cytotoxic T lymphocytes (CTL), which recognize class I major histocompatibility complex (MHC) loci, express the T cell differentiation antigen T8. However, a minority of T8+ CTL clones was found to recognize class II MHC antigens. To test the hypothesis that T8 is involved only in T cell recognition of class I MHC antigens, we studied the role of T8 in the cytotoxic activity of class II MHC-specific CTL. Monoclonal antibodies specific for T8 blocked the activity of most class I MHC-specific CTL clones but did not affect the activity of class II MHC-specific CTL clones. Moreover, a mild trypsin treatment of the clones, which removed and T8 determinant, affected the activity of class I MHC but not that of class II MHC-specific CTL clones. These findings indicate that the class II-specific MHC CTL clones described here did not require T8 for their cytolytic activity. The activity of one T8+ class I MHC-specific (HLA-B27) CTL clone (HG-61) against the B cell line JY, which was used to raise this CTL clone, was not blocked by trypsin treatment of this clone. However, the activity of CTL clone HG-61 against target cells different from JY but carrying the appropriate HLA specificity was blocked by anti-T8 antibodies and trypsin treatment. The implications of these findings for the hypothesis that T8 is involved only in the activity of CTL with a relatively low avidity for class I MHC antigens are discussed.

Antibodies, Monoclonal↗
PubMed1987

Endocytosis and de novo expression of major histocompatibility complex encoded class I molecules: kinetic and ultrastructural studies.

The endocytic pathway and expression of the major histocompatibility complex encoded class I molecule H-2Kk was investigated in murine fibroblasts. Internalization of H-2K molecules did not occur constitutively. Endocytosis of the molecules was induced by addition of multivalent ligands such as rabbit anti-mouse immunoglobulin serum or protein A-bearing liposomes to cells pretreated with anti-H-2Kk antibodies. The complete removal of H-2K molecules took about 5 h at 37 degrees C and was not inhibited by the lysosomotropic agent NH4Cl or the protein synthesis inhibitor cycloheximide. When targeted liposomes that contained carboxyfluorescein at a self-quenched concentration were directed against H-2K molecules, the cells became highly fluorescent after 30 min: a consequence of carboxyfluorescein release from the liposomes. This process was inhibited by NH4Cl but not by cycloheximide, suggesting internalization of H-2K molecules into acidic intracellular compartments. The endocytic pathway of liposomes directed against H-2K molecules and the subcellular compartments involved in this process were investigated with targeted liposomes containing horseradish peroxidase. By electron microscopy, the endocytic process was shown to start very rapidly (1-2 min) and involved uncoated cell surface invaginations. The cytoplasmic uncoated vesicles fused together into larger vacuoles containing concentrated liposomes and by 1 h, liposomes began to be destroyed in lysosomal compartments. Within 4 h, 90% of liposomes were lysed inside the cell. The fate of radiolabeled anti-H-2K antibody was also investigated. Degradation of the antibody occurred only when cross-linked with a second layer of antibody, beginning after 2 h and becoming more pronounced after 20 h of incubation. The original cell surface abundance of H-2K molecules was reestablished after 5 to 7 h. During this time neither NH4Cl nor cycloheximide had any effect on the cell surface expression of the molecule. However, after a second cycle of internalization, cells incubated with cycloheximide no longer expressed these molecules. These results suggested that H-2K molecules were not recycled back to the surface after internalization but were degraded in lysosomal compartments together with their ligand. Preexisting molecules, already present in intracellular pools, were expressed to replace them. By immunoprecipitation of metabolically labeled intracellular and surface H-2K molecules, we observed an intracellular pool of H-2K of about 70 to 80% of the total cellular H-2K.

Animals↗
PubMed1994

Antigen expressed by Salmonella typhimurium is processed for class I major histocompatibility complex presentation by macrophages but not infected epithelial cells.

Macrophages were shown to mediate class I major histocompatibility complex (MHC-1) presentation of a fusion protein (Crl-OVA) expressed in Salmonella typhimurium, a bacterium which fails to escape from vacuolar compartments after phagocytosis or penetration into host cells. Salmonella typhimurium also penetrates into non-phagocytic intestinal epithelial cells, a portal of entry for systemic infection. We tested the ability of infected epithelial cells to process antigen expressed by S. typhimurium for presentation by MHC-I molecules to CD8+ T cells. CMT-93 murine adenocarcinoma cells expressed Kb and effectively presented the OVA 257-264 peptide to CD8 OVA T-hybridoma cells, but infected CMT-93 cells failed to process Crl-OVA expressed in S. typhimurium. Therapeutically useful MHC-I-restricted cytotoxic T-lymphocyte (CTL) responses may be generated by macrophage presentation of Salmonella antigens or recombinant antigens expressed in Salmonella vaccine vectors. Our data suggest that an inability of epithelial cells to present these antigens may limit the utility of CTL in epithelial immunity in salmonellosis, but studies of additional epithelial cell systems are needed.

Animals↗
PubMed1996

Induction of humoral immune tolerance to major histocompatibility complex antigens by transfusions of UVB-irradiated leukocytes.

To determine whether immune tolerance to donor major histocompatibility complex (MHC) antigens can be induced by transfusions of UVB-irradiated leukocytes, studies were conducted in inbred strains of mice with well-characterized MHC antigens. CBA mice with H-2k phenotype and BALB/c mice with H-2d phenotype were used as recipients and donors, respectively. Humoral immune tolerance is defined as absence of antibody response after challenge with transfusions of untreated donor leukocytes. It was found that transfusions of purified peripheral blood mononuclear leukocytes irradiated with 1,200 mJ/cm2 UVB not only prevented allo-immunization but also induced humoral immune tolerance to donor class-I and -II MHC antigens in all recipient mice. Donor plasma and platelets interfered with the induction of this tolerance. The tolerance induction by UVB-irradiated leukocytes is dose-dependent. Four weekly transfusions of 2 x 10(5) leukocytes were required to ensure tolerance induction in all mice. The results of a long-term follow-up study showed that the induced tolerance is long-lasting and can withstand repeated challenges by untreated donor leukocytes. Recipient mice tolerant to H-2d antigens also became tolerant to H-2b, H-2r, and H-2n MHC antigens but did not have impaired antibody responses to antigens unrelated to donor leukocytes. Adoptive transfer experiments showed the development of negative regulatory cells in spleens of the tolerized mice. In view of recent feasibility of using UVB-irradiated human platelet concentrates for prevention of HLA alloimmunization, the findings of this study support that UVB-irradiated donor leukocytes could have potential, important clinical application in transplantation medicine.

Adoptive Transfer↗