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PubMed2006

Minor histocompatibility antigens: from transplantation problems to therapy of cancer.

The idea of transferring healthy marrow for the therapeutic treatment of the various diseases of the blood and of the immune system made a significant contribution to controlling diseases and to advancing modern clinical sciences. The first series of bone marrow transplantations in the 1960s were confronted with severe complications. It became clear that matching for the human leukocyte antigen (HLA) system between donor and recipient significantly improved the clinical results. Nonetheless, an unacceptable percentage of severe complications remained that is mainly attributable to non-HLA histocompatibility systems, i.e., minor histocompatibility antigens. Observations in the 1970s that minor histocompatibility antigens cause serious problems in human bone marrow transplantation laid the basis for their use as curative antigens in stem cell transplantation to date. Thus, the allo-immune T cell activities caused by minor histocompatibililty antigen disparities between HLA-matched donor and recipient can now be applied for the benefit of the transplant patient.

Bone Marrow Transplantation↗
PubMed1996

HLA types in women with cervical human papillomavirus (HPV) lesions prospectively followed up for 10 years.

Certain genotypes of HPV have been recently implicated in the etiology of carcinoma of the uterine cervix. In order to determine whether HLA antigen-controlled immunoregulatory functions have a role in the pathogenesis of HPV infections, class I and II HLA antigen typing was carried out on a series of 96 randomly selected women who were part of a cohort of 530 women prospectively followed up for cervical HPV infections in our clinic since 1981. The frequency of the DQ3 antigen, which has previously been reported to be increased among cervical cancer patients, was decreased in our HPV patients compared with the control group of Finnish women, but it was slightly increased in HPV16-infected women (P = 0.0812). However, we were able to demonstrate that HLA-DR5 antigen is significantly increased (i) in patients with high grade cervical intraepithelial neoplasia (CIN) (P < 0.02), and (ii) in women harbouring the high risk HPV type 16 (P = 0.0003), thus confirming earlier reports of an association of this HLA antigen and cervical cancer. Such a close association between the high risk HPV type 16 with an HLA antigen might have important implications in the possible immunogenetic basis of the increased risk for squamous cell carcinoma of the uterine cervix.

Cytotoxicity Tests, Immunologic↗
PubMed1991

Platelet crossmatching with lymphocytotoxicity test: an effective method in alloimmunized Chinese patients.

Fifty-three patients receiving long-term platelet transfusions were regularly screened for platelet-associated antibodies by a platelet suspension immunofluorescence test (PSIFT) and a lymphocytotoxicity test (LCT). Subsequently, 24 patients became alloimmunized; all of their antibodies were of HLA specificity. Eighty-two single-donor platelet transfusions were given, and the clinical responses were considered satisfactory if the 18-hour corrected count increment was 7.5 x 10(3) per microL or higher. In the meantime, 82 pairs of patient sera and donor lymphocytes were crossmatched. Among 63 crossmatched transfusions, 53 (84%) resulted in a satisfactory increment, with a mean (+/- SEM) of 17.71 +/- 1.96 (x 10(3)/microL), and 10 did not result in a satisfactory increment. The increments after 19 unmatched transfusions and 25 random-donor (uncrossmatched) transfusions were 0.7 +/- 0.3 and 2.39 +/- 0.66, respectively. The difference was not significant (p greater than 0.05). The agreement between the LCT results and clinical response was 88 percent. Retrospectively, the corrected count increments showed no significant differences (p greater than 0.05) among three groups of HLA grading: the increments for A/BU/BX, C/D, and random HLA matches were 22.97 +/- 4.07, 15.1 +/- 1.97, and 14.85 +/- 2.04, respectively. These results suggest that platelet crossmatching by LCT is an effective method for use in alloimmunized patients, especially Chinese patients.

Blood Grouping and Crossmatching↗
PubMed2003

The role of regulatory cells in miniature swine rendered tolerant to cardiac allografts by donor kidney cotransplantation.

To determine the mechanism by which cotransplantation of a kidney allograft induces tolerance to a donor heart in miniature swine, we examined the role of CD25+ cells in heart/kidney recipients. Tolerance was induced to class-I MHC mismatched hearts by cotransplanting a donor-specific kidney with a 12-day course of cyclosporine. Peripheral blood leukocytes (PBL) were isolated from tolerant heart/kidney recipients and used in cell-mediated lympholysis (CML) coculture assays as either unmodified PBL, PBL enriched for CD25+ cells or PBL depleted of CD25+ cells to assess their ability to suppress CML responses of naïve recipient-matched leukocytes against mismatched target cells. Primed PBL from tolerant heart/kidney recipients completely suppressed lysis by naïve cells. Complete suppression of the response of naïve recipient-matched leukocytes against donor-matched target cells was lost following the depletion of CD25+ cells from tolerant heart/kidney animal PBL, but it was reestablished by incubation of naïve cells with small populations of CD25+ cells from tolerant heart/kidney animals. These data suggest that peripheral blood from tolerant heart/kidney recipients contains regulatory cells that, upon priming, can suppress the response of naïve-matched PBL in coculture CML assays, and that suppression appears to be dependent on cells expressing CD25.

Animals↗
PubMed1978

Immunologic factors determining survival of cadaver-kidney transplants. The effect of HLA serotyping, cytotoxic antibodies and blood transfusions on graft survival.

We assessed immunologic factors determining graft survival in 510 recipients of primary cadaver allografts at one center. The degree of HLA match grade did not directly affect graft survival (54 per cent in no-antigen match, and 42 per cent in three-antigen match, at two years). There was no correlation between the HLA match grade and the degree of stimulation of the mixed lymphocyte culture. Patients receiving more than five blood transfusions had a significantly better graft survival than nontransfused recipients (52 versus 23 per cent, respectively, at two years, P less than 0.001). The beneficial effect of transfusions was noted whether or not lymphocytotoxic antibodies were produced, provided adequate screening was performed before transplantation. Transfusions did not alter the degree of stimulation in the mixed lymphocyte culture. More liberal use of transfusions and frequent screening for cytotoxic antibodies would probably result in more effective cadaver-kidney transplantation.

Blood Transfusion↗
PubMed2002

Characterization of the expression of MHC proteins in human embryonic stem cells.

Human embryonic stem (ES) cells are pluripotent cells that may be used in transplantation medicine. These cells can be induced to differentiate into cells from the three embryonic germ layers both in vivo and in vitro. To determine whether human ES cells might be rejected after transplantation, we examined cell surface expression of the MHC proteins in these cells. Our results show very low expression levels of MHC class I (MHC-I) proteins on the surface of human ES cells that moderately increase on in vitro or in vivo differentiation. A dramatic induction of MHC-I proteins was observed when the cells were treated with IFN-gamma but not with IFN-alpha or -beta. However, all three IFNs induced expression of MHC-I proteins in differentiated human ES cells. MHC-II proteins and HLA-G were not expressed on the surface of undifferentiated or differentiated cells. Ligands for natural killer cell receptors were either absent or expressed in very low levels in human ES cells and in their differentiated derivatives. In accordance, natural killer cytotoxic assays demonstrated only limited lysis of both undifferentiated and differentiated cells. To initiate a histocompatibility databank of human ES cells, we have isotyped several of the published ES cell lines for their human leukocyte antigens. In conclusion, our results demonstrate that human ES cells can express high levels of MHC-I proteins and thus may be rejected on transplantation.

Cell Differentiation↗
PubMed1990

Susceptibility or resistance to lysis by alloreactive natural killer cells is governed by a gene in the human major histocompatibility complex between BF and HLA-B.

The specificity recognized on normal allogeneic cells by a given alloreactive (1-anti-A) natural killer clone is controlled by a gene locus termed EC1. Because the EC1 locus was previously shown to be located on chromosome 6, families characterized by a recombinant major histocompatibility complex haplotype were analyzed to map this locus more precisely. The breakpoint of recombination was studied by standard HLA typing, complement typing, and restriction fragment length polymorphism analysis of a series of genes located between the complement cluster genes and HLA-B within the major histocompatibility complex region. Three of 10 families analyzed were informative. From the data obtained, the EC1 locus maps between BF and HLA-B and presumably is one of the normal genes recently described in this region.

Antigens, Differentiation↗
PubMed1993

Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.

Allograft rejection is a T cell-dependent process. Productive T cell activation by antigen requires antigen engagement of the T cell receptor as well as costimulatory signals delivered through other T cell surface molecules such as CD28. Engagement of CD28 by its natural ligand B7 can be blocked using a soluble recombinant fusion protein, CTLA4Ig. Administration of CTLA4Ig blocks antigen-specific immune responses in vitro and in vivo, and we have shown that treatment of rats with a 7-d course of CTLA4Ig at the time of transplantation leads to prolonged survival of cardiac allografts (median 30 d), although most grafts are eventually rejected. Here, we have explored additional strategies employing CTLA4Ig in order to achieve long-term allograft survival. Our data indicate that donor-specific transfusion (DST) plus CTLA4Ig can provide effective antigen-specific immunosuppression. When DST is administered at the time of transplantation followed by a single dose of CTLA4Ig 2 d later, all animals had long-term graft survival (> 60 d). These animals had delayed responses to donor-type skin transplants, compared with normal rejection responses to third-party skin transplants. Furthermore, donor-matched second cardiac allografts were well tolerated with minimal histologic evidence of rejection. These data indicate that peritransplant use of DST followed by subsequent treatment with CTLA4Ig can induce prolonged, often indefinite, cardiac allograft acceptance. These results may be clinically applicable for cadaveric organ and tissue transplantation in humans.

Abatacept↗
PubMed1998

A comparative study of major histocompatibility complex and red blood cell antigen phenotypes as risk factors for recurrent urinary tract infections in women.

Recurrent urinary tract infections (RUTI) are a significant health problem for many women, and host characteristics that increase susceptibility are not completely defined. This study evaluated data from 99 patients to examine further the question of a possible association between major histocompatibility complex (MHC) or red blood cell (RBC) antigen phenotype and predisposition to RUTIs. MHC class I and II, ABO, and Lewis RBC phenotypes were determined serologically. The MHC class II phenotypes of 55 subjects were also determined by DNA polymerase chain reaction techniques. There were no significant differences in the proportions of HLA-A or -B antigen types between patients and controls, nor in the frequencies of serologically or DNA-defined HLA-DR or -DQ phenotypes. Patient ABO and Lewis RBC phenotypes were not statistically different than those for controls. Thus, the overall risk for women to develop RUTIs does not appear to be associated with any single HLA, ABO, or Lewis phenotype.

ABO Blood-Group System↗
PubMed2000

A method for estimating the intensity of overdominant selection from the distribution of allele frequencies.

A method is proposed for estimating the intensity of overdominant selection scaled by the effective population size, S = 2Ns, from allele frequencies. The method is based on the assumption that, with strong overdominant selection, allele frequencies are nearly at their deterministic equilibrium values and that, to a first approximation, deviations depend only on S. Simulations verify that reasonably accurate estimates of S can be obtained for realistic sample sizes. The method is applied to data from several loci in the major histocompatibility complex (Mhc) in numerous human populations. For alleles distinguished by both serological typing and the sequence of the peptide-binding region, our estimates of S are comparable to those obtained by analysis of DNA sequences in showing that selection is strongest on HLA-B and weaker on HLA-A, HLA-DRB1, and HLA-DQA1. The intensity of selection on HLA-B varied considerably among populations. Two populations, Native American and Inuit, showed an excess rather than a deficiency in homozygosity. Comparable estimates of S were obtained for alleles at Mhc class II loci distinguished by serological reactions (serotyping) and by differences in the amino acid sequences of the peptide-binding region (molecular typing). A comparison of two types of data for DQA1 and DRB1 showed that serotyping led to generally lower estimates of S.

Algorithms↗
PubMed1998

Impaired renal graft survival after a positive B-cell flow-cytometry crossmatch.

BACKGROUND: The clinical and immunological relevance of a positive B-cell flow-cytometry (B-FCXM) crossmatch in renal transplantation is still controversial. METHODS: We retrospectively analysed 145 consecutive cadaveric renal transplantations performed from May 1991 to September 1995 in our institution. All grafts were transplanted following a negative IgG T-cell complement-dependent cytotoxicity crossmatch (T-CDCXM). Concomitantly to CDCXM, B-cell and T-cell FCXM were performed and results were expressed as a mean fluorescence index (FI). Two groups were compared: 116 recipients grafted with a negative B-FCXM vs a group of 19 patients grafted with a positive B-FCXM. RESULTS: The two groups were similar for length of cold ischaemia, donor and recipient's age and degree of HLA mismatching. The proportion of patients with pre-transplant anti-HLA class I antibodies or a retransplantation was significantly increased in the positive B-FCXM group vs the negative B-FCXM group. Recipient survival at 48 months was not significantly different in the two groups. However, graft survival at 12 and 48 months was significantly poorer in the positive B-FCXM than in negative B-FCXM (68% vs 90% at 12 months: P = 0.007, and 57% vs 79% at 48 months: P = 0.02). Within the positive B-FCXM group, no differences were found in pre-transplant anti-HLA class I or II alloimmunization as well as retransplantation frequency between the patients who lost their graft and the patients who did not. CONCLUSION: Our results suggest that a pretransplant positive B-FCXM is associated with an impaired long-term graft survival in renal allotransplantation.

Antibodies↗