The functional polymorphisms of VDR, GC and CYP2R1 are involved in the pathogenesis of autoimmune thyroid diseases.

Vitamin D is a multi-functional immune regulator, and a low serum concentration of vitamin D promotes autoimmune inflammation. In this study, we evaluate the association between the prognosis of autoimmune thyroid disease (AITD) and the functional polymorphisms of genes that regulate vitamin D metabolism. For 139 Graves' disease (GD) patients, 116 Hashimoto's disease (HD) patients and 76 control subjects, we genotyped the following polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP): vitamin D receptor (VDR): rs731236, rs7975232, rs2228570 and rs1544410; group-specific component (GC): rs7041 and rs4588; and CYP2R1: rs10741657. The frequency of the TT genotype for the rs731236 polymorphism was higher in GD patients than in HD patients (P = 0·0147). The frequency of the C allele for the rs7975232 polymorphism was higher in GD patients than in control subjects (P = 0·0349). The proportion of GD patients whose anti-thyrotrophin receptor antibody (TRAb) level was >51% was higher in those with the CC genotype than in those with the CA+AA genotypes (P = 0·0065). The frequency of the CC genotype for the rs2228570 polymorphism was higher in HD patients than in control subjects (P = 0·0174) and GD patients (P = 0·0149). The frequency of the Gc1Gc1 genotype for the GC polymorphism and the AG genotype for the CYP2R1 polymorphism were lower in intractable GD than in GD in remission (P = 0·0093 and 0·0268, respectively). In conclusion, genetic differences in the VDR gene may be involved in the development of AITD and the activity of GD, whereas the genetic differences in the GC and CYP2R1 genes may be involved with the intractability of GD.

Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograft recipients.

BACKGROUND: Several conventional forms of immunosuppression have been shown to antagonize the efficacy of anti-CD154 monoclonal antibody- (mAb) based costimulatory molecule blockade immunotherapy. Our objective was to determine if allograft recipients treated with a conventional immunosuppressive regimen could be sequentially converted to anti-CD154 mAb monotherapy without compromising graft survival. METHODS: Outbred juvenile rhesus monkeys underwent renal allotransplantation from MHC-disparate donors. After a 60-day course of triple therapy immunosuppression with steroids, cyclosporine, and mycophenolate mofetil, monkeys were treated with: (1) cessation of all immunosuppression (control); (2) seven monthly doses of 20 mg/kg hu5C8 (maintenance), or; (3) 20 mg/kg hu5C8 on posttransplant days 60, 61, 64, 71, 79, and 88 followed by five monthly doses (induction+maintenance). Graft rejection was defined by elevation in serum creatinine>1.5 mg/dl combined with histologic evidence of rejection. RESULTS: Graft survival for the three groups were as follows: group 1 (control): 70, 75, >279 days; group 2 (maintenance): 83, 349, >293 days, and; group 3 (induction+maintenance): 355, >377, >314 days. Acute rejection developing in two of four monkeys after treatment with conventional immunosuppression was successfully reversed with intensive hu5C8 monotherapy. CONCLUSIONS: Renal allograft recipients can be successfully converted to CD154 blockade monotherapy after 60 days of conventional immunosuppression. An induction phase of anti-CD154 mAb appears to be necessary for optimal conversion. Therefore, although concurrent administration of conventional immunosuppressive agents including steroids and calcineurin inhibitors has been shown to inhibit the efficacy of CD154 blockade, sequential conversion from these agents to CD154 blockade appears to be effective.

Induction of donor-specific hyporesponsiveness and prolongation of cardiac allograft survival by jejunal administration of donor splenocytes.

BACKGROUND: Donor-specific immunosuppression is important in transplantation surgery. We examined the immunosuppressive effects of donor splenocytes administered postoperatively into the jejunum and the effect of such treatment on the survival of heterotopic vascularized cardiac allograft in rats. METHODS: Lewis (LEW, RT-1l) recipient rats were treated with 5x10(7) Brown Norway (BN, RT-1n) donor splenocytes for 5 days orally, intrajejunally, or subcutaneously. The immune responses of LEW treated with either donor BN or irrelevant Wistar King A (WKA, RT-1k) were examined by mixed lymphocyte reaction (MLR) and delayed type hypersensitivity (DTH). The effect of postoperative enteral treatment for 6 days with suboptimal dose of cyclosporine (CsA) on heterotopic cardiac allotransplantation was investigated. We measured the production of cytokines (interleukin [IL]-2, IL-4, IL-10, and interferon-gamma [IFN-gamma]) in the supernatant of MLR by ELISA. The effect of intravenous dose of GdCls to block Kupffer cell function was also investigated before the administration of splenocytes. RESULTS: MLR and DTH responses were strongly inhibited in a BN-restricted manner after jejunal or oral feeding of donor BN splenocytes but not by subcutaneous injection or injections by any routs of WKA splenocytes. The effect was more prominent in jejunal than oral feeding. Immunosuppression was associated with a significant inhibition of IL-2 and IFN-gamma production and increased concentrations of IL-4 and IL-10 in MLR supernatants. Immunosuppression was abrogated by pretreatment with GdCl3. Postoperative intrajejunal feeding of donor splenocytes with CsA significantly prolonged cardiac allograft survival time (18.7+/-7.3 vs. 9.9+/-1.7 days for control animals). CONCLUSION: Jejunal administration of splenocytes produces donor-specific immunosuppression and prolongs cardiac allograft survival. Our results suggest the involvement of T helper (Th) 2 cytokines and Kupffer cells in the induction of immune hyporesponsiveness, and indicate that this method represents a unique approach for induction of donor-specific immunosuppression.

[Phase II study of 5-FU tablet in bladder tumor].

A phase II study of 5-FU tablet at a dose of 200 to 300 mg/day (b.i.d. or t.i.d.) for 28 patients with tumor of urinary bladder was undertaken by a cooperative study group consisting of 7 institutions including Okayama University. The clinical response rate in 25 evaluable cases was 20.0 (5/25) (CR: 2 cases, PR: 3 cases, MR: 4 cases, NC: 11 cases and PD: 5 cases). Efficacy rates of 5-FU tablet were higher in patients having smaller lesions or those who received no previous chemotherapy. Some adverse effects were observed in 6 of 27 cases (22.2%), all of which were gastrointestinal symptoms. Abnormal laboratory tests were seen in 18.5%, but all of these abnormalities were mild. 5-FU tablet administered to patients with tumor of urinary bladder was found to be highly distributed in tumor tissue. It is considered from the above results that 5-FU tablet is one of the useful agents for tumor of urinary bladder.

Quantitative analysis by digital computer of 99mTc-N-pyridoxyl-5-methyltryptophan (99mTc-PMT) hepatogram in diffuse parenchymal liver diseases.

99mTc-N-pyridoxyl-5-methyltryptophan (99mTc-PMT) hepatograms were analyzed to provide information about the liver and bile duct. Calculations were based on a four compartmental model and included corrections for blood, tissue, hepatic parenchymal and bile backgrounds. The time activity curves for 99mTc-PMT in the cardiac region were described as the sum of two exponential functions, while curves for the hepatic regions were described as the sum of three exponential components. The measured hepatograms were compared with simulations and good agreement between the two curves showed that the compartmental model adequately described the blood and bile activities in vivo. Hepatic excretion rate constants were 0.179 +/- 0.026 in three normal subjects, 0.102 +/- 0.012 in four patients with chronic hepatitis and 0.082 +/- 0.034 in six patients with liver cirrhosis. In the case of diffuse parenchymal liver disease, there were lower rate constants for the excretion from the liver to the bile ducts than in normals, and the relative distribution volumes were also larger than normal. Prior to the development of this compartmental model, no useful kinetic model had been found which could satisfactorily explain the time activity curves. Experience in human studies proves this method to be accurate in determining the rate constants for the hepatobiliary transport of 99mTc-PMT.