PubMed Health⌕ Search

Biomedical subjects

A Madrigal

Publications and source records attributed to A Madrigal.

25 records · Page 2Linked to original sources
PubMed1996

HLA-DPB1 mismatch at position 69 is associated with high helper T lymphocyte precursor frequencies in unrelated bone marrow transplant pairs.

HLA incompatibility between bone marrow recipient and unrelated donor pairs is often associated with severe acute graft-versus-host disease following bone marrow transplantation. Due to the extensive polymorphism of HLA genes, finding genotypically identical pairs is a difficult challenge. Therefore, it is crucial to single out the relevance of each HLA gene and, within each sequence, the polymorphic positions that induce a T-cell response. Among HLA class II genes, the relevance of HLA-DPB1 in inducing graft-versus-host disease is still controversial. In this study, we selected 37 bone marrow transplant pairs on the basis of HLA class I A and B identity as determined by isoelectric focusing and of class II identity as determined by serology and by low-resolution genomic typing. We analyzed them for the possible relationship between frequency of cytotoxic T lymphocyte and helper T lymphocyte precursors (CTLp and HTLp, respectively) and genomically determined class II mismatches. Seventeen pairs had high numbers of both CTLp and HTLp. They were not further considered because of the difficulty in determining whether the T-cell response was induced by class I or class II mismatches. Of the remaining pairs with low CTLp and high HTLp, six had disparities at HLA-DRB1 and HLA-DPB1 genes, and 14 differed only at the HLA-DPB1 locus. Among the latter pairs, we found a correlation between HLA-DPB1 mismatches and HTLp frequency, thus suggesting that disparity at this locus influences the alloreactive T-cell response. When the HTLp frequency was correlated with each single mismatch found in the 14 pairs, it appeared that the nature of the amino acid at position beta69 played a relevant role in inducing alloreactivity.

Bone Marrow Transplantation↗
PubMed1994

Distinct T cell populations distinguish chronic myeloid leukaemia cells from lymphocytes in the same individual: a model for separating GVHD from GVL reactions.

Donor lymphocyte responses to minor histocompatibility antigen (mHA) differences are involved in allo-responses between HLA matched pairs causing GVHD and graft-versus-leukaemia (GVL). Since some mHA are tissue-restricted, GVHD and GVL responses may be separable. We studied donor lymphocyte responses to patients with CML in a series of 10 HLA-matched sibling and 10 unrelated donor-recipient pairs comparing proliferation to recipient PHA blasts and CML cells and attempting to selectively deplete responses to PHA blasts in vitro. Responses in counts per min (c.p.m) to CML cells and PHA blasts were, respectively, 2809 +/- 2205 (SD) and 7376 +/- 1877 in related and 12,107 +/- 7191 and 26,136 +/- 22,479 in unrelated pairs. Autologous responses to PHA blasts were significantly lower (mean 779 +/- 735) (p < 0.001). Results correlated with clinical outcome: higher responses to recipient cells correlated with transplant-related death (p = 0.02 for CML and p = 0.06 for PHA blasts). Higher responses to CML correlated with GVHD grade > or = II (p = 0.025). Donor lymphocytes exposed to recipient PHA blasts for 5 days and treated with a ricin-conjugated anti-CD25 antibody retained over 75% of their response to CML but < 10% to PHA blasts. Similarly, depletion of response to CML but not to PHA blasts occurred when CML was the primary challenge. These results indicate that distinct populations of donor T cells respond to recipient leukaemic and non-leukaemic cells, and provide the basis for a clinically applicable technique to selectively deplete donor GVHD reacting cells while conserving GVL.

Graft vs Host Disease↗
PubMed1990

Cytotoxic T cell recognition of an endogenous class I HLA peptide presented by a class II HLA molecule.

Human leukocytes were stimulated in vitro with peptides corresponding in sequence to the highly variable helix of the alpha 1 domain of various HLA-B and -C molecules. A CD4+ CD8- cytotoxic T cell line, CTL-AV, that is specific for the HLA-B7 peptide presented by HLA-DR11.1 was obtained. The HLA-DR11.2 molecule, which only differs at three residues from HLA-DR11.1, did not present the HLA-B7 peptide to CTL-AV. Peptides from the alpha 1 domain helix of other HLA-A and HLA-B molecules, but not HLA-C molecules, competed with the HLA-B7 peptide for binding to HLA-DR11.1. A cell line (WT50) that coexpresses HLA-B7 and HLA-DR11.1 was killed by CTL-AV in the absence of any added HLA-B7 peptide. The processing and presentation of HLA-B7 in these cells appears to be through the endogenous, and not the exogenous, pathway of antigen presentation. Thus, Brefeldin A inhibits presentation and chloroquine does not. Furthermore, introduction of purified HLA-B7 molecules into HLA-DR11.1+, HLA-B7- cells by cytoplasmic loading via osmotic lysis of pinosomes, but not by simple incubation, rendered them susceptible to CTL-AV killing. These results provide an example of class II major histocompatibility complex (MHC) presentation of a constitutively synthesized self protein that uses the endogenous pathway of antigen presentation. They also emphasize the capacity for presentation of MHC peptides by MHC molecules.

Anti-Bacterial Agents↗
PubMed1989

Molecular analysis of the HLA-DR5 haplotype.

A panel of eleven HLA-DR5 homozygous lymphoblastoid cell lines was investigated for structural heterogeneity on the product level. HLA class II antigens were isolated by immunoprecipitation with different anti-class II monoclonal antibodies and separated by two-dimensional (2-D) gel electrophoresis. As a result, three distinct DRB1, one commonly expressed DRB3, and two distinct DQ gene products could be identified that combined to four different haplotypes associated with HLA-DR5. A hitherto serologically undetected split of HLA-DRw11 was presented by three cell lines. HLA-DRw11 and HLA-DRw12 were found to be related allospecifities that differ only in their DRB1 locus products, but are closely associated with the supertypic DRB3 allele HLA-DRw52b and with HLA-DQw7. The DRB3 alleles HLA-DRw52a and DRw52c were not detected in our cell line panel, indicating that these supertypic determinants are in negative linkage disequilibrium with HLA-DR5. Our data suggest that intra HLA-DR/DQ crossing-over events contribute to the development of the HLA class II polymorphism. Evidence is presented that the T cell defined HLA-D allospecifities are commonly determined by DRB1 and DQ gene products.

Amino Acids↗
PubMed1986

Monoclonal antibodies to HLA-DP-transfected mouse L cells.

Mouse L cells transfected with human HLA-DP (DPw4) alpha and beta genes were used to make monoclonal antibodies in C3H mice. A polymorphic antibody, DP11.1, was obtained, as well as several monomorphic antibodies. In ELISAs, DP11.1 bound to DPw4 cells and, more weakly, to DPw2, but not DPw1, -3, -5, or -6, using HLA homozygous cells. It also bound to L-cell transfectants expressing either DPw2 or DPw4 products. From B lymphoblastoid cell lysates labeled with [35S]methionine, the antibody immunoprecipitated alpha and beta chains of a similar size to those precipitated by a well-characterized DP monoclonal antibody, B7/21.2. Immunoblotting indicated that the DP11.1 antibody was directed against the alpha chain. This result confirms partial sequence data that showed that the DP alpha chain, as well as DP beta, is polymorphic, and that DPw2 and -4 alpha chains are very similar, if not identical.

Animals↗