James F. Mowbray

A subset of patients with recurrent spontaneous abortion is deficient in transforming growth factor β-2-producing suppressor cells in uterine tissue near the placental attachment site

PROBLEM: To determine if patients with unexplained recurrent miscarriage have a deficiency of decidual immunosuppressor cells that produce transforming growth factor β type 2, as has been found in mice with abortion due to rejection and/or trophoblast failure.

Psycho-Neuro-Cytokine/Endocrine Pathways in Immunoregulation During Pregnancy

PROBLEM: Some mammalian pregnancy failure is thought to occur by immunological or immunologically modifiable mechanisms. The original model wherein spontaneous abortion was proposed to represent rejection of the conceptus as an allograft has been supplanted by a model of maternal paraimmunological natural effector cell toxicity to fetal trophoblast more closely related to tumor rejection. The problem is to integrate current information concerning the role of immunological, paraimmunological, endocrinological, and stress‐triggered neural factors that determine whether or not abortion will occur.

Derivation and Biochemical Characterization of an Enterovirus Group-Specific Monoclonal Antibody

This paper describes the derivation and characterization of monoclonal antibodies reactive with the group-specific epitopes of the VP1 peptide shared by enteroviruses. When tested against a wide range of the prototype strains of Coxsackie viruses A and B, polioviruses, and echoviruses, the monoclonal antibodies reacted with all of them in two or more assay systems. The virus of hepatitis A was the only enterovirus tested which was not recognized by these monoclonal antibodies. This finding is consistent with recent reports demonstrating genomic dissimilarity between this virus and the other enteroviruses. Although monoclonal antibodies have frequently been found to be assay specific, these particular antibodies were found to be equally effective in different immunochemical and biological assay systems. Biochemical characterization of one of these monoclonal antibodies is described and its potential usefulness for diagnosis is discussed.

Enzyme replacement therapy by fibroblast transplantation: long-term biochemical study in three cases of Hunter's syndrome.

We have assessed the effectiveness of transplanted histocompatible fibroblasts as a long-lived source of lysosomal enzymes for replacement therapy in three patients with Hunters syndrome, over periods ranging from 2.5 to 3.75 yr. The level of Hunter corrective factor excreted by all three patients increased after transplantation, as did the activity of alpha-L-idurono-2-sulfate sulfatase in serum, when measured directly with a radioactive disulfated disaccharide substrate. Sulfatase activity was also raised in leukocyte homogenates from the two patients that we were able to assess. These increases in enzyme activity were accompanied by corresponding increases in catabolism of heparan and dermatan sulfates, as shown by (a) a decrease in sulfate:uronic ratios of urinary oligosaccharides, (b) an increase in iduronic acid monosaccharide, and (c) a normalization of Bio-Gel P-2 gel filtration profiles. Both the increase in enzyme activity and increased catabolism were maintained during the period of study and were not affected by either a gradual decrease or total withdrawal of immunosuppressive therapy.

Enzyme replacement therapy by fibroblast transplantation in a case of Hunter syndrome

SUPPLEMENTATION of deficient enzymes essential for complete catabolism of glycosaminoglycans (GAG) has been used with limited success in several types of mucopolysaccharidosis1–4. The beneficial effects and concomitant changes in urinary GAG after this form of treatment, however, have been only transient, presumably because of the short life in vivo of the enzymes involved5–7. Because of this limitation, we recently tried, by means of skin transplantation, to provide a more permanent source of corrective enzymes in a patient with Hunter syndrome8. Although two HLA antigens from each donor were incompatible with those of the patient and both grafts had been visibly rejected within 3 months, there was a marked increase in breakdown and excretion of GAG subsequent to treatment, which lasted for more than 9 months. In addition, the activity of Hunter corrective enzyme isolated from the patients urine, was also significantly increased. We attributed the effectiveness of the skin transplant to the release of Hunter corrective factor by donor cells and its uptake by host cells, in a manner analogous to that described for fibroblasts in vitro9–11. We have now attempted to increase further both the effectiveness and longevity of replacement therapy, using fully histocompatible skin fibroblasts injected sub-cutaneously as a source of corrective enzyme. An advantage of this procedure is that surgery is not required and it would in principle be applicable to other genetic deficiency diseases of lysosomal enzymes.

Clinical and Research Application of an Enterovirus Group-Reactive Monoclonal Antibody

Diagnostic methods employed in enterovirus laboratories are generally laborious, slow and expensive. This is largely because type-specific neutralization tests still play the major role in identification and diagnostic serology. In the companion paper we describe the derivation of monoclonal antibodies against epitopes of the VPI peptide which are shared by all of the enteroviruses tested to date, with the exception of hepatitis A virus. This study describes the application of one of these monoclonal antibodies in several research and diagnostic procedures, illustrating a special utility in a wide variety of assay systems. This monoclonal antibody has proved particularly useful in the detection of enterovirus antigens in circulating immune complexes, and in identifying field isolates of this group of viruses. Immunohistochemistry, previously almost impossible in enterovirus diagnosis and research due to the large number of serotypes, is now shown to be practical and informative when this monoclonal antibody is used.

Immunosuppressive properties of monoclonal antibodies and human polyclonal alloantibodies to the R80K protein of trophoblast.

PROBLEM: The R80K protein on human trophoblast is antigenically polymorphic, and in all placentae of successful pregnancies, the protein is covered by maternal alloantibody. Alloantibody eluted from human placenta has been shown to inhibit killing by human NK cells. Do those antibodies to R80K that inhibit NK killing also affect the murine abortion models?

An 80-kDa Syncytiotrophoblast Alloantigen Bound to Maternal Alloantibody in Term Placenta

PROBLEM: We have shown that most of the IgG present on term syncytiotrophoblast, membrane, microvesicles is bound to an 80 kDa protein antigen (R80K).

Maternal Response to Paternal Trophoblast Antigens

PROBLEM: What is the function of the immunoglobulin (Ig) G antibody bound to trophoblast in normal pregnancy, and what is the antigen?

GENETIC CONTROL OF PROGRESSIVE AUTONOMIC FAILURE: EVIDENCE FOR AN ASSOCIATION WITH AN HLA ANTIGEN

In 16 patients with progressive autonomic failure, a rare disease of unknown cause, the frequency of the HLA antigen Aw32 was 13 times more common than in healthy controls, giving a relative risk of progressive autonomic failure with Aw32 of 28.7. Such genetic predisposition to the disease might cause a defect of catecholamine metabolism In the brain or possibly affect the immune response to a virus.