Brenda Nisperos

Marrow Transplantation from Related Donors Other Than HLA-Identical Siblings

Marrow transplantation has generally been limited to patients with a sibling who is genotypically identical for HLA. In a study of the acceptable limits of HLA incompatibility, 105 consecutive patients with hematologic cancers who received marrow grafts from haploidentical donors (study group) were compared with 728 similar patients concurrently receiving grafts from HLA genotypically identical siblings (control group). The unshared haplotypes differed variably: 12 were phenotypically but not genotypically identical for HLA-A, HLA-B, and HLA-D; 63 differed at one locus (A, B, or D); 24 at two loci; and 6 at three. A higher proportion of study patients had delayed engraftment, granulocytopenia, or graft rejection. Acute graft versus host disease occurred earlier and with greater frequency in study patients. The risk of the disease did not correlate with disparity for Class I (A or B) versus Class II (D-region) loci. Thus, incompatibility for HLA has an important effect on the course after clinical marrow transplantation. In spite of these complications, there was no statistically significant difference in the survival of the study patients and control patients who received their transplants during remission.

Effect of HLA Compatibility on Engraftment of Bone Marrow Transplants in Patients with Leukemia or Lymphoma

We analyzed the relevance of HLA compatibility to sustained marrow engraftment in 269 patients with hematologic neoplasms who underwent bone marrow transplantations. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, B, and D antigens of the haplotype not shared. These 269 patients were compared with 930 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. The rate of graft failure was 12.3 percent among the recipients of marrow from a donor with only one identical haplotype, as compared with 2.0 percent among recipients of marrow from a sibling with the same HLA genotype (both haplotypes inherited from the same parents) (P less than 0.0001). The incidence of graft failure correlated with the degree of donor HLA incompatibility. Graft failure occurred in 3 of 43 transplants (7 percent) from donors who were phenotypically HLA-matched with their recipient (haplotypes similar, but not inherited from the same parents), in 11 of 121 donors (9 percent) incompatible for one HLA locus, in 18 of 86 (21 percent) incompatible for two loci, and in 1 of 19 (5 percent) incompatible for three loci (P = 0.028). In a multivariate binary logistic regression analysis, independent risk factors associated with graft failure were donor incompatibility for HLA-B and D (relative risk = 2.1; 95 percent confidence interval, 1.7 to 2.5; P = 0.0004) and a positive crossmatch for anti-donor lymphocytotoxic antibody (relative risk = 2.3; 95 percent confidence interval, 1.8 to 2.8; P = 0.0038). Residual host lymphocytes were detected in 11 of 14 patients with graft failure, suggesting that the mechanism for graft failure could be host-mediated immune rejection. We conclude that donor HLA incompatibility and prior alloimmunization are significant risk factors for graft failure, and that a more effective immunosuppressive regimen than those currently used is needed for consistent achievement of sustained engraftment of marrow transplanted from donors who are not HLA-identical siblings.

Maternal-Fetal Disparity in HLA Class II Alloantigens and the Pregnancy-Induced Amelioration of Rheumatoid Arthritis

BACKGROUND Rheumatoid arthritis frequently remits during pregnancy, for unknown reasons. Since an immune response to paternally inherited fetal HLA can occur during normal pregnancy and since rheumatoid arthritis is an autoimmune disorder with a known HLA class II antigen association, we tested the hypothesis that maternal-fetal disparity in HLA alloantigens might be associated with the pregnancy-induced remission of rheumatoid arthritis. METHODS We studied 57 pregnancies of 41 women with rheumatoid arthritis, 18 prospectively and 39 retrospectively. Serologic and DNA techniques were used to study HLA class I and II antigens. For newborns, typing was performed from cord-blood samples obtained at delivery. For four young children, typing was performed from DNA extracted from hair samples. RESULTS We found significantly more maternal-fetal disparity in HLA-DR and DQ antigens in pregnancies characterized by the remission or improvement of rheumatoid arthritis than in pregnancies characterized by active disease. Further studies using DNA-typing techniques to define allelic variants of HLA-DR and DQ antigens confirmed this observation. Maternal-fetal disparity in alleles of HLA- DRB1, DQA, and DQB occurred in 26 of 34 pregnancies characterized by remission or improvement (76 percent), as compared with 3 of 12 pregnancies characterized by active arthritis (25 percent) (odds ratio, 9.7; P = 0.003). The difference between the two groups was most marked for alleles of HLA-DQA. CONCLUSIONS Amelioration of rheumatoid arthritis during pregnancy is associated with a disparity in HLA class II antigens between mother and fetus. These findings suggest that the maternal immune response to paternal HLA antigens may have a role in the pregnancy-induced remission of rheumatoid arthritis.

Analysis of the HLA-DRw8 haplotype: recognition by HTC typing of three distinct antigen complexes in Caucasians, Native Americans, and Orientals.

We have used seven HLA-D homozygous typing cells (HTC) in a comparative study of the DRw8 antigen complex in three racial groups. Three distinct HLA-D specificities were recognized, each associated with HLA-DRw8. Four of the HTC defined a DRw8-associated HLA-D specificity designated 8.1, one defined a specificity designated 8.2, and two defined a specificity designated 8.3. Each of the three spec cities showed an association with a distinct racial group: Dw“8.1” in Caucasians, Dw“8.2” in Pacific Northwest Indians, and Dw“8.3” in Orientals. An informative primed lymphocyte (PLT) cell generated against a Dw“8.1” haplotype was able to distinguish 8.1 from 8.2 and 8.3. Using selected anti-DRw8 sera, a serologic distinction between 8.1 and 8.3 could also be made. It was thus possible, by using both cellular and serologic techniques in a comparative population study, to recognize at least three HLA-D-defined splits of the DRw8 haplotype.

Remission of Rheumatoid Arthritis During Pregnancy and Maternal-Fetal Class II Alloantigen Disparity

ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disorder known to be associated with specific class II genes. Although it has been known since 1938 that the majority of women with RA experience disease improvement or remission during pregnancy, the reasons remain unknown. Pregnancy represents an immunologic challenge and maternal immune recognition of the semi‐allogeneic fetus occurs as part of normal pregnancy. We hypothesized that maternal immune response to fetal HLA antigens might be associated with the effect of pregnancy on arthritis activity. To test this hypothesis, we studied HLA antigens in mother‐child pairs comparing maternal‐fetal HLA antigen sharing for pregnancies where arthritis improved with those where disease was active. No significant difference was observed in the two groups for class I HLA antigens. Fetal‐maternal disparity for HLA‐DR and HLA‐DQ antigens was observed significantly more frequently in pregnancies with remission or improvement compared with those in which disease was active. These observations suggest that maternal immune response to fetal paternally‐inherited class II HLA antigens may be important in RA remission observed during pregnancy.

Unique sequences for two HLA-DRB1 genes expressed on distinct DRw6 haplotypes.

We have used restriction fragment length polymorphism (RFLP) analysis and DNA sequencing to characterize two distinct DRB1 alleles expressed on DRw52 and DQw7-associated haplotypes but not readily defined by conventional DR serology. These two haplotypes, designated HLA-D “HAG” and “PEV”, react variably with DRw13(w6), DRw14(w6), and the more broad DR “3+6” antisera. Analysis of RFLP revealed that HLA-D “HAG” and “PEV” are associated with different DRw52 variants, and that “HAG” is indistinguishable from DRw18(3) haplotypes. Sequencing of the “HAG” and “PEV” DRB1 genes showed each to represent novel alleles. Nevertheless, these sequences show similarities with the other alleles of the DR5, w6, and w8 family. “HAG” (DRB1*1303) appears to have arisen either from two recombinational events involving at least three DRB1 sequences (DRB1*1101, DRB1*0803, DRB1*0401) or from a single recombinational event together with multiple point mutational events. “PEV” appears to represent a DRB1*1301-1302/DRB1*1101 recombinant allele, with recombination having occured in the region of bases 175 – 198. The results of this study suggest that the DRw52 family haplotypes is derived from a relatively restricted number of ancestral sequences, with diversity among DRB1 alleles within this family arising through gene conversion or recombination events.