Demonstration of three anomalous plasma proteins induced by a vitamin K antagonist.

With the aid of precipitating antibodies against the bovine coagulation factors II, IX, and X three immunologically non-identical proteins can be demonstrated that are induced by the administration of a vitamin K antagonist (phenprocoumon). Each of these proteins is immunologically identical to one of three coagulation factors mentioned. The proteins differ from normal coagulation factors (a) by a lack of biological activity; (b) by a faster anodic migration rate in the presence of Ca2+. The proteins appear in the plasma concomitantly with the decrease of the normal factor.

Improved patient and graft survival after treatment of acute rejections of cadaveric renal allografts with rabbit antithymocyte globulin.

In a prospective randomized trial, we compared the effectiveness of rabbit antithymocyte globulin (RATG) in the treatment of acute renal allograft rejection with the results of treatment by high oral doses of prednisone. Fifty recipients of cadaveric kidneys were included in each group. In the RATG group, the prednisone dose was not increased and a dose-by-rosette protocol was used to keep T cell levels between 50 and 150/mm. The three-month and one-year graft survival rates in the RATG group were 84% and 78%, and were significantly higher than those in the prednisone group (64% and 50%). A significant difference in patient survival could also be detected. In the RATG group the three-months and one-year patient survival rates were 100% and 98%, and patient survival rates in the prednisone group were 91% and 84%, respectively. The percentage of second rejections was higher in the prednisone group and 70% of these patients showed a good response to subsequent RATG treatment. Renal function after six months was similar in both groups. No serious side effects were encountered in the RATG group. The incidence of infections was the same in both groups. Treatment of acute rejections with RATG is preferable to prednisone treatment. It improves long-term graft and patient survival and is steroid-sparing.

HLA-DRW6 and treatment of acute rejection with antithymocyte globulin.

The influence of DRw6-antigen on graft survival was studied in a single-center study in 223 recipients of a cadaveric kidney. Although graft survival in 148 DRw6-negative recipients was not significantly different from that in 75 DRw6-positive recipients, the percentage of patients without a rejection episode in the first three months after grafting was significantly less in the DRw6-negative recipients (p = 0.03). In DRw6-positive patients who had received rabbit antithymocyte globulin (RATG) as the first antirejection treatment, graft survival was significantly better than in prednisone-treated DRw6-positive recipients. In the DRw6-negative patients RATG treatment also gave better results, but these differences were not significant. When RATG-treated patients were excluded from the analysis, the difference in graft survival between DRw6-negative and DRw6-positive patients became apparent (p = 0.03). These findings show that the negative influence of the DRw6 antigen present in the recipients is counterbalanced by the beneficial effect of RATG treatment for first rejection episodes.

Treatment of acute rejection of cadaveric renal allografts with rabbit antithymocyte globulin.

In a prospective randomized single-blind trial, we compared the effectiveness of rabbit antithymocyte globulin (RATG) in the treatment of acute renal graft rejection with the results of treatment by high oral doses of prednisone. Twenty recipients of cadaveric kidneys were included in each group. In the RATG group, the prednisone dose was not increased and a dose-by-rosette protocol was used to keep T cell levels between 50 and 150/mm3. In this group 15 of the 20 patients responded to the treatment. One of these patients lost her kidney afterward because of a technical failure. In five patients rejection was irreversible despite a subsequent course of high-dose prednisone orally. In the prednisone group, 13 patients showed a good response, but 3 of them only after a subsequent course of RATG. The remaining seven patients underwent nephrectomy before a course of RATG could be given. One patient in this group died of septicemia. In either group there were six second rejection episodes, but they developed 2.2 months later in the RATG group. All second rejection episodes were treated with the alternative regimen and all patients responded to this treatment. Renal function after 6 months was similar in both groups. Less infections occurred in the RATG group. Prior to rejection, there were no differences in concentrations of peripheral T cells between both groups. Treatment of acute rejections with RATG is an effective and safe procedure which is steroid sparing.

Complete nucleotide sequence of HLA-B*0703, a B7 variant (BPOT).

HLA-B703 (BPOT) is a B7-like antigen segregating within families. To determine the complete B*0703 nucleotide sequence, HLA-ABC-cDNAs derived from the EBV cell line POT71 have been cloned. Four B*0703-positive clones were sequenced to obtain an accurate consensus sequence. With respect to the isoelectric focusing-identical HLA-B*0702 allelic product, HLA-B*0703 differed only in a cluster of four nucleotide substitutions in exon 2 and a single (silent) nucleotide substitution in exon 3. The resulting amino acid substitutions in the alpha 1 domain of B703 at residues 69 (Ala-->Thr), 70 (Gln-->Asn), and 71 (Ala-->Thr) probably have their origin in a segmental exchange between B7 and other B alleles.

Effect of intensive immunosuppression on the course of chronic progressive multiple sclerosis.

39 patients with chronic-progressive multiple sclerosis were treated with a short course of intensive immunosuppression in high doses of cyclophosphamide and prednisone. The follow-up period varied between 1 and 5 years with a mean of 21/2 years. Progression of the disease ceased in 27 patients for varying periods, with a mean of two years. In 13 patients the progression ceased during the whole follow-up period. The treatment gave the most favourable results in patients who were DRw2 positive in histocompatibility testing, whose disease started at an early age (around 28 years), whose disease duration before treatment was short (6 years), whose progression was fast and whose disability before treatment was low. If CSF levels of IgG3 months after the treatment remain low, this is a sign of good prognosis.

HLA-typing and lymphocyte population studies in patients with multiple sclerosis.

Compared to a control population, the frequency of HLA-B7 was increased in a group of 46 patients with a chronic progressive form of multiple sclerosis (MS) (RR = 2.9, P = 0.01). Significance of the association was lost after correction for first order error. Results on serotyping for "B-cell DW2" antigen are suggestive of an increased frequency of this antigen in chronic progressive MS patients (RR = 2.9, P = 0.01). The percentage of T-cells (E-rosette forming lymphocytes) in MS patients was lower (mean 46 +/- 17%, n = 34) than in a control group (mean 62 +/- 10%, n = 90). Only 5 of the 40 patients had high B-lymphocyte percentages, whereas no difference in B-cell counts was observed between the total group of patients and the control group. The T- and B-lymphocyte ratio in the MS patients was lower than in the control group. The 7 patients, with the lowest T/B-cell ratio were negative for "B-cell DW2" antigen. In 3 patients, the sum of T plus B-lymphocytes was far lower than 90%. At least 4 patients had in their serum antibodies against autologous lymphocytes as found by immunofluorescence tests. No correlation could be found between these serological and immunological data and clinical data on progression of the disease, the IgG in CSF and improvement after immunosuppressive treatment.

Influence of HLA-DRW6 in the recipient on occurrence of acute rejection of first renal allografts: beneficial influence of antithymocyte globulin as antirejection treatment.

In a retrospective analysis of 232 recipients of first cadaveric kidney grafts the percentage of patients without an acute rejection was significantly higher in DRW6-negative than in DRW6-positive patients. This was not reflected in a better graft survival rate. This discrepancy was probably caused by the kind of antirejection treatment used. In DRW6-positive patients who had received RATG as the initial treatment for rejection, graft survival was significantly better than in DRW6-positive recipients treated with high doses of prednisone. In the DRW6-negative patients RATG treatment gave also better results, but here the difference was not significant. These findings show that the negative influence of the DRW6 antigen present in the recipients was counterbalanced by the beneficial effect of RATG-treatment for first rejection episodes. No influence of DR matching could be detected.

HLA associations in aurothioglucose- and D-penicillamine-induced haematotoxic reactions in rheumatoid arthritis.

HLA phenotype frequencies were studied in 21 rheumatoid arthritis (RA) patients with haematotoxic reactions to aurothioglucose (AuTG) or D-penicillamine (DP), 65 matched RA controls and 277 healthy controls. Antigens B8 and DR3 were significantly increased in the toxic RA patient group as compared to both RA controls and healthy controls. These contrasts were strongest in the patients with AuTG-induced thrombocytopenia or leucopenia: all patients developing either reaction to this drug were B8- and/or DR3-positive (p less than 0.001), 7 (78%) being positive for both antigens. In the patient group with DP-induced reactions these antigens were also increased but these differences were not significant. In the latter group the prevalence of antigen DR4 was high, especially in the patient group with DP-induced thrombocytopenia, all 12 patients with this type of reaction being DR4 positive. Our data suggest that haematotoxic reactions to AuTG and DP develop primarily (or even exclusively) in genetically predisposed RA patients. Furthermore, the HLA phenotype contributing to an increased risk seems not to be the same for the two anti-rheumatic drugs studied.

Immunogenetic heterogeneity of seronegative rheumatoid arthritis and the antiperinuclear factor.

HLA typing was carried out in 132 patients with rheumatoid arthritis (RA) with long term follow up, and special attention was focused on rheumatoid factor negative patients. The patients were divided into four groups: 55 patients with a seropositive RA and a positive antiperinuclear factor (group A); 39 seropositive patients but a negative antiperinuclear factor (group B); 14 patients consistently seronegative for 3-28 years (mean 11.8 years) but positive for antiperinuclear factor (group C); patients consistently negative for 3-28 years (mean 11.8) and also negative for antiperinuclear factor (group D). The prevalence of HLA-DR4 was 31/55 (56%), 29/39 (74%), 10/14 (71%), and 9/24 (37%) for groups A, B, C, and D respectively, and in all groups was significantly higher than in 277 healthy controls (55/277, 20%). No significant difference was found between seropositive (groups A and B) and seronegative (groups C and D) patients, but groups A, B, and C had higher prevalences than group D. It is concluded that in seronegative RA HLA-DR4 is preferentially associated with the antiperinuclear factor positive group.

HLA-B SNA antigen: a BW6 associated B locus antigen belonging to the B5 CREG.

A new B locus antigen has been found in members of two unrelated families and in a patient originating from Morocco belonging to the Berber population. A complete analysis has been performed with antisera from the 9th and 10th IHWS defining the B5 CREG antigens. Serology, absorption experiments and family studies indicate that SNA antigen is a Bw6 associated subtype of B5 antigen closely related to but clearly distinct from each of the B5 CREG antigens. One-dimensional isoelectric focusing study (1D-IEF) confirms that the SNA antigen precipitates as a B locus gene product and has an isoelectric point identical to that of Bw52 and one of the charge variants of B51.

Adult-onset Still's disease. Disease course and HLA associations.

Disease course and HLA antigens were determined in 29 patients with definite and 13 patients with probable adult-onset Still's disease (AOSD). Twenty-six patients had persistent disease with continuous disease activity for at least 1 year. Radiographic examination revealed evidence of joint destruction in 26 patients. In 15 patients, at least 1 root joint was impaired. The frequency of DR4 was increased in the total group of patients (35%, P = 0.03) and in the 29 patients with definite AOSD (41%, P = 0.02) compared with the frequency in normal controls (20%). None of the patients was positive for DR1, and only 1 was positive for Bw35. The frequency of DRw6 was increased in the patients with involvement of at least 1 root joint (40%, P = 0.03) compared with the patients without involvement of these joints (11%).