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PubMed2001

MHC matching and mechanisms of alloactivation in corneal transplantation.

BACKGROUND: In human corneal transplantation the value of matching, particularly for MHC class II, is unclear and controversial. The contribution of the direct pathway to T cell activation is also uncertain. We have determined the relative contribution of class I, II and non-MHC antigens to graft rejection and of the direct and indirect pathways to T cell activation in a rat model mimicking human incompatibilities. METHODS: DA (RT1a) strain recipients received fully mismatched PVG (RT1c) strain grafts or grafts from one of three recombinant strains bearing DA MHC genes on a PVG background. Graft survival was assessed and the specificity of T cells generated in the draining lymph nodes was determined in mixed lymphocyte (MLR) proliferation assays. To assess the contribution of the direct pathway, fully mismatched graft were performed and allospecific proliferation was measured after depletion of recipient APC from the MLR reaction. RESULTS: There was no significant difference in survival of grafts between the four grades of mismatch, which ranged from a full mismatch to non-MHC mismatches alone (median survival 12.5, 11, 13 and 12.5 days respectively). In conformity with clinical results, strong secondary responses were generated against targets matched for MHC with the recipient. Depletion of recipient APC from a fully allogeneic secondary MLR did not fully abrogate donor-specific proliferation. CONCLUSIONS: Class II matching is of no benefit in this model. Strong indirect responses to non-MHC mismatches are sufficient to induce the rapid rejection, but the small numbers of class II+ cells in the donor appear sufficient to generate a direct response.

Animals↗
PubMed2003

Donor-specific tolerance in fully major histocompatibility major histocompatibility complex-mismatched limb allograft transplants under an anti-alphabeta T-cell receptor monoclonal antibody and cyclosporine A protocol.

BACKGROUND: Recent studies have demonstrated that treatment with alphabeta-T-cell receptor (TCR) monoclonal antibody and cyclosporine A (CsA) can extend survival in composite tissue allografts (CTA). The purpose of this study was to induce tolerance in fully major histocompatibility complex (MHC)-mismatched rat limb allografts under 7 days of a combined alphabeta-TCR-CsA protocol. METHODS: The authors performed 30 hind-limb allotransplantations across the MHC barrier between Brown Norway donors (BN; RT1n) and Lewis recipients (LEW; RT1l). Isograft and allograft controls received no treatment. The experimental groups received monotherapy of alphabeta-TCR and CsA or a combination of alphabeta-TCR and CsA for 7 days only. Donor-specific tolerance and immunocompetence were determined by standard skin grafting in vivo and mixed lymphocyte reaction (MLR) in vitro. The efficacy of immunosuppressive therapy and the level of donor-specific chimerism were determined by flow cytometry. RESULTS: Long-term survival (>350 days) was achieved in allograft recipients (n=6) under the 7-day protocol of combined alphabeta-TCR-CsA. Donor-specific tolerance and immunocompetence of long-term chimeras were confirmed by acceptance of skin grafts from the donors and rejection of the third-party alloantigens (AxC Irish). At day 120, MLR demonstrated unresponsiveness to the host and donor antigens but strong reactivity against third-party alloantigens. Flow cytometry confirmed the high efficacy of immunosuppressive treatment and the development of donor-specific chimerism (7.6% of CD4+-RT1n+ cells, 1.3% of CD8+-RT1n+ cells, and 16.5% of CD45RA+-RT1n+ cells) in the periphery of tolerated recipients. CONCLUSIONS: Combined therapy of alphabeta-TCR-CsA for 7 days resulted in tolerance induction in fully MHC-mismatched rat hind-limb allografts. Tolerance was directly associated with stable, donor-specific chimerism.

Animals↗
PubMed2004

Impact of donor-recipient MHC matching on experimental islet allotransplant survival in naïve and presensitized Lewis rats.

In human islet transplantation (ITX), the impact of donor-recipient major histocompatibility complex (MHC) matching on transplant survival is currently unknown. Utilizing defined MHC mismatches, we have investigated the outcome of ITX in naïve and presensitized congenic Lewis rats. ITX into streptozotocin diabetic Lewis rats was performed under the kidney capsule. Presensitization by skin transplantation was performed on days 1, 28, and 56, followed by ITX on day 84. Survival was greatest in isolated MHC class I mismatches, followed by isolated MHC class II mismatches. The shortest transplant survival was observed following full MHC mismatched ITX (P<0.05 vs. isolated MHC class I or II). Following recipient presensitization, islets in general showed reduced survival compared to naïve recipients. In this congenic rat model, islet transplant survival was significantly influenced by the degree of donor-recipient MHC matching, as well as by recipient presensitization. These data suggest that MHC matching might be useful in human islet transplantation.

Animals↗
PubMed1977

Evidence for two series of B-cell antigens in man and their comparison with HLA-D.

Population and family studies of five sera with antibodies against B-cell determinants show an excellent fit of some of them with the HLA-D determinants, suggesting that the HLA-D determinants themselves or closely linked structures can be recognized by serology. One serum, Ag, might be coded for by a locus different from HLA-D, which could be located between HLA-A and -B. A two-color fluorescence test to detect B-cell antigens was used and found to save time and reagents and to give very good results.

B-Lymphocytes↗
PubMed1977

Cellology of HLA. 22. Heterogeneity of cellular reactions in negative HLA-D typing.

We have demonstrated that in more than half of the mixed lymphocyte reactions, proliferative reactions, in which responders were reacted against HLA-D-compatible homozygous typing cells, were significantly greater than zero. These reactions often masked the true HLA-D identity of the cells under test, as was subsequently shown by primed lymphocyte testing.

HLA Antigens↗
PubMed1975

Studies on recombination within the mouse H-2 gene complex. III. Further serological analyses of the H-2t haplotypes.

The five H-2t haplotypes are all intra-H-2 recombinants which have identical K and D regions, but differ in the central regions of the complex. Analyses of H-2, Ia and Ss-Slp types indicate that the crossover in H-2t1 took place between the K and I regions, in the H-2t2 between G and D, in H-2t3 and H-2t4 between the I-B and I-C subregions and in H-2t5 between I and S. The set of recombinants will be very valuable for studies of traits which map in the I and S regions.

Animals↗
PubMed1978

Tuberculosis associated with HLA--B8, BfS in a Newfoundland community study.

In three adjacent Newfoundland communities comprising some 1500 people, 589 people have been HLA typed. Forty-six of the typed people gave a history of previous clinical tuberculosis which required treatment. Fifty-six percent of the TB patients carried HLA B8 compared with 20% of the remainder of the population. This is a highly significant difference (P less than 0.01). In each community the frequency of B8 as an epidemiological marker correlated with the incidence of tuberculosis. B8 is associated with TB in ths study with a relative risk of 5.2 which compares with combined relative risks in the literature for coeliac disease and Addison's disease of 9.5 and 6.4, respectively, and which is greater than the risks for all the other B8-related diseases. The factor B allele, Bf S, was found on all the B8 haplotypes, but the overall Bf gene frequencies in tuberculosis patients did not deviate from expected values.

Cytotoxicity Tests, Immunologic↗
PubMed1978

Low responsiveness in MLC induced by certain HLA--A antigens on the stimulator cells.

An individual, BK, repeatedly gave typing responses against homozygous typing cells representing more than two HLA--D antigens. Family studies showed that she had inherited the HLA--Dw2 and Dw7 determinants, in agreement with results from primed lymphocyte typing. The HLA--A, B, C types of the stimulators giving rise to unexpected typing responses all involved the HLA--A1, A3 or A11 antigens. The hypothesis of this specificity in low-responsiveness was confirmed in the independent stimulator sample provided by the 7th workshop homozygous typing cell panel. The same pattern was observed when BK was tested as a responder towards related and unrelated heterozygous stimulators. Furthermore, in three-cell experiments it was found that BK cells were able to suppress the response to the Dw-identical individual, BS, towards stimulators carrying HLA--A1, A3, or A11. This effect of BK's cells appeared to be radiosensitive. We were not able to demonstrate suppressive supernatant factors in the relevant cultures, neither were we able to find circulating cytotoxic cells by the direct CML-technique, nor an accelerated cytotoxic response by the indirect CML-technique against targets carrying HLA--A1 or A3. This is the first demonstration of induction of suppressor cells in MLC by HLA--A, B, C antigens in the stimulator cells.

Adult↗
PubMed1978

RhLA complex of Rhesus monkeys. X. Implications of the association between D and Ia1 locus antigens.

A high association has been found between D-locus determinants defined by cellular methods (typing cells) and the serologically defined B cell or Ia antigens controlled by the Ia1 locus. Data from recombinant offspring in two rhesus families place the Ia1 locus within RhLA, in the close vicinity of the D or major MLC locus. In fact, identity between the products of those two loci cannot be excluded. Further, it was shown that cells proven to be homozygous for Ia1 antigens, are nearly always typing cells (and therefore homozygous for D-locus determinants) and, conversely, that proven typing cells carry only a single Ia1 antigen and are thus probably homozygous for Ia1 products. In addition, it could be demonstrated that matching for Ia1 antigens greatly facilitates the detection of unrelated individuvals who are mutually non-reactive in MLC. This "predictive value" of Ia1 matching has important implications for the selection of optimal donors for organ transplantation.

Animals↗
PubMed1978

A haplotype study of HLA complex with special reference to the HLA-DR series and to Bf. C2 and glyoxalase I polymorphisms.

Fifty-three French families were typed for alleles at seven loci of the HLA complex (HLA-A, -B, -C, -DR, -Bf, -C2 and -GLO) and 212 haplotypes were demonstrated. Eleven recombinations were observed (two A/B, two A/C, two B/Bf, one Bf/D and four D/GLO). The linkage disequilibrium was calculated not only between two alleles (delta) but between three, four...seven alleles (D). In order to compare the intensity of D values in the various haplotypes, the influence of the differences in gene frequencies was eliminated by the introduction of the standardized Ds (Ds = D/D max). The number of haplotypes in disequilibrium is relatively limited since most of the significant Ds involved about 17 haplotypes. For some haplotypes, the disequilibrium covered the whole distance from A to GLO but the stronger disequilibrium concerns the C to Bf or C to DR segment. Three hypotheses (isolation, admixture of population and selection) concerning the formation and maintenance of the disequilibria are discussed.

Epitopes↗