N. Kaibara

Limb allografts in rats immunosuppressed with FK506. I: Reversal of rejection and indefinite survival

We have tested the effects of FK506 (FK), a new immunosuppressive agent, on a rat limb allograft model. Histoincompatible BN limb allografts were rejected in untreated F344 hosts within 11±1 days (mean ± SD) after operation. A single injection of 2 mg/kg, 10 mg/ kg, or 50 mg/kg of FK on the day of limb transplantation (day 0) significantly prolonged graft survival in a dose-dependent manner—i.e., mean limb survival times (MST) based on gross signs of skin rejection were 16±3 days, 51 ±6 days, or 104±17 days, respectively (P < 0.01). Delayed treatment with a single injection of 10 mg/kg of FK at when early signs of rejection were visible (day 7 or day 10) reversed the ongoing rejection. The MSTs in these groups were comparable to that of those treated with the same dosage of FK on day 0. The FK-induced unresponsiveness toward limb allografts was donor-specific because limb-allografted, FK-protected rats could not accept the skin grafts from a third-party donor. In the next set of experiments, rats were given a single administration of 10 mg/kg of FK on the day of limb allograft, followed by intermittent injections of 3 mg/kg of FK once a week. This regimen produced complete graft survival for more than 200 days, though Pneumocyatis carinii pneumonia occurred in most of the recipients. These results represent the unique effects of FK in preventing or reversing the graft rejection and in inducing indefinite survival in this animal model of composite tissue allografts.

Limb allografts in rats immunosuppressed with cyclosporine: as a whole-joint allograft.

We performed limb allografts in three inbred rat strains immunosuppressed with cyclosporine. As controls, 10 autografts and 10 isografts exhibited an excellent result. In minor-mismatched allografts (Lewis to Fischer, n = 45), with the use of cyclosporine, the grafted limbs survived and the articular cartilage retained normal architecture and cell viability 52 weeks after grafting, but without cyclosporine treatment severe degeneration and destruction of articular cartilage were shown by 16 weeks after operation. In major-mismatched allografts (Brown Norway to Fischer, n = 35), the articular cartilage of cyclosporine-treated animals maintained normal architecture and cell viability 52 weeks after operation despite the gross appearance of skin rejection, while that of non-cyclosporine-treated animals was degenerated and destroyed by 6 weeks. These results suggest the possibility of whole-joint allografts in humans with the use of cyclosporine, as well as other organ transplantations.

Serum transfer of collagen arthritis to cyclosporin-treated, type II collagen-tolerant rats

Collagen arthritis has been passively transferred with a serum concentrate from immunized donors to immunologically naive recipients as well as cyclosporin-treated, type II collagen-tolerant rats. These findings point to an important role for anticollagen antibody and appear to rule out a role for cellular immunity to type II collagen in the initiation of this disease. The passively transferred arthritis was a transient lesion in the majority of naive recipients and in the cyclosporin-treated, type II collagen-tolerant rats as well when a serum concentrate was transferred after the cessation of cyclosporin treatment. When cyclosporin-treated, type II collagen-tolerant rats received transfer concentrate while cyclosporin was administered continuously, arthritis was significantly enhanced, and lasted as long as cyclosporin was administered and in the majority of rats up to 2 weeks after the cessation of cyclosporin treatment. These results, together with a rapid clearance of anticollagen antibody from the serum, suggest that anticollagen antibody is not the sole regulatory factor and that a cellular suppressor system, sensitive to cyclosporin, might participate in the regulation of this disease process.

Intermediate form of osteopetrosis with recessive inheritance

The clinical and radiographic features of the intermediate form of osteopetrosis in two sibs are presented in which the disorder appears to have been inherited as a recessive trait. Although this form of osteopetrosis has been poorly delineated, its recognition is practically important in order to give an accurate prognosis. This paper also presents an unusual complication of bilateral avascular necrosis of the femoral head in the younger sib. Radiographic changes of the femoral heads suggest those of Legg-Calvé-Perthes disease, though the possibility of avascular necrosis following unrecognized femoral neck fracture is not completely excluded.

Spondyloepiphyseal dysplasia tarda with progressive arthropathy

The clinical and roentgenographic manifestations of six cases suffering from spondyloepiphyscal dysplasia tarda with progressive arthropathy are presented. The roentgenographic features consist of generalized platyspondyly and varying degrees of epiphyseal involvement with conspicuous enlargement of both ends of the short tubular bones of the hands. This disorder appears at an earlier age, and is more crippling than the usual form of spondyloepiphyseal dysplasia tarda. It is suggested that orthopaedic measures are essential for all patients with this disorder, as profound disability may be expected by progressive involvement of the major joints.

Phalangeal microgeodic syndrome in childhood: Report of seven cases and review of the literature

Seven cases of phalangeal microgeodic syndrome in childhood are reported. Reviewing the literature, we have found a total of thirty Japanese cases, including the cases of our own. On the other hand, only ten cases have been reported outside Japan. The mean age of onset of the Japanese cases was six and a half years, which is older than that in the initial description. Of further interest is the fact that all the cases in Japan occurred sporadically and exclusively in winter, and regressed spontaneously and fairly rapidly within six months. Furthermore, most of the cases reported in Europe also occurred in the winter months. These facts imply an etiological relationship between the lowered temperature and the bone lesions.

Effects of deoxyspergualin on collagen arthritis in mice

We have studied the effect of the immunosuppressive agent deoxyspergualin (DSG) on collagen arthritis in mice. DSG, when given prophylactically, was capable of suppressing the development of collagen arthritis in mice as well as the immunological response to native type II collagen in a dose-dependent manner. Further, treatment of DSG, started 7 days after the primary immunization, also resulted in the inhibition of development of arthritis and immunity to collagen. The treatment of DSG, started after a booster injection, did not suppress the development of arthritis, despite suppression of antibody production in collagen. These findings suggest the possibility that a threshold level of anti-type II collagen antibodies may exist which must be exceeded before arthritis develops. Its therapeutic use in mice did not affect the clinical course of arthritis or the immune response to collagen, which is similar to the results obtained with cyclosporin.

Socket and cup surface replacement of the hip.

To improve the surgical results of severe osteoarthritis of the hip, surface replacement of the hip using a double cup without cement was employed on 75 hips during the period from 1972 to 1977. The results of the procedures have been analyzed on 67 hips followed for more than 6 months. The most dramatic improvement following the procedure has been pain relief, observed in 58 of 67 hips (86%). Three reoperations were necessary. Failures were treated satisfactorily either by total hip replacement, or by arthrodesis and/or by placing a new cup on the head respectively. There was no operative death, pulmonary embolism, thrombophlebitis, nor deep infection. We do not think this procedure replaces more definitive surgery such as the Charnley-type total hip replacement, but it is a good adjunctive procedure particularly in patients younger than 60 years of age.

Suppression of collagen arthritis in rats by heterologous anti-idiotypic antisera against anticollagen antibodies

Affinity-purified rat anti-type II collagen antibodies were used to prepare anti-idiotypic antibodies in rabbits. It has been demonstrated that such anti-idiotypic antibodies are capable of binding to anti-type II collagen antibodies in vitro. Intravenous administration of heterologous anti-idiotypic antisera at the time of immunization with type II collagen resulted in a significant suppression of anti-type II collagen antibody formation and the development of arthritis, although delayed-type hypersensitivity skin test response to type II collagen was not affected. However, treatment of rats with heterologous anti-idiotypic antisera at Day 7 after immunization was ineffective in altering disease expression. On the other hand, treatment with heterologous anti-idiotypic antisera had no significant suppressive effect on the incidence or severity of adjuvant arthritis. These results indicate that the effect of heterologous anti-idiotypic antisera directed toward anti-type II collagen antibodies is disease specific and is restricted to collagen arthritis.

Comparative studies of the effects of FK506 and cyclosporin A on passively transferred collagen-induced arthritis in rats

We investigated the effect of a novel immunosuppressive agent, FK506, in comparison with cyclosporin A (CsA) on the development of passive arthritis induced by anti-type II collagen (CII) antisera in rats. FK506 pretreatment shortly before serum transfer markedly suppressed the incidence and the severity of passive arthritis, while CsA pretreatment had no observable effects on this disease when used in doses sufficient to suppress the development of active arthritis induced by CII immunization. In an additional study, we examined whether these agents affect antibody-mediated tolerance induction. CII-specific immunological tolerance was induced by serum transfer, but was unaffected by either FK506 or CsA pretreatment in our regimen. While its precise mechanism of the immunosuppressive activity remains to be elucidated, FK506 can act on the antibody-mediated effector phase of arthritis and may offer new insights into the possible role of potential therapeutic utility in human autoimmune diseases.