Biomedical subjects
Publications and source records attributed to I R Mackay.
Prenatal cytomegalovirus (CMV) infection associated with severe brain damage was detected in an infant whose mother had been treated with prednisolone and azathioprine for systemic lupus erythematosus (SLE). Serology showed that maternal CMV infection had been acquired at least four months before pregnancy. Screening for CMV infection in pregnant women receiving immunosuppressive drugs is recommended.
A radioisotopic index test was used to detect that time of onset and intensity of cell-mediated immune inflammation of experimental autoimmune encephalomyelitis (EAE) in mice. Mice were tested at various time intervals after an encephalitogenic immunization with mouse spinal cord to homogenate for delayed-type hypersensitivity (DTH) to myelin basic protein (MBP) by intradermal challenge with antigen in the ear pinna. After 25 hr, the intensity of DTH was measured by 125I-radiometry which depends upon the migration of 125I-UdR radiolabeled mononuclear cells into the antigen depot. Cells reactive to MBP were detected by the ear assay as early as 7 days after the initial encephalitogenic sensitization. The degree of cell-mediated immune inflammation in the brain and spinal cord during the evolution of EAE was also measured by a radioisotopic technique; increased 125I-UdR uptake could be detected in the brain 3 to 4 days before the onset of signs of EAE at days 11 to 12, whereas 125I-UdR in the spinal cord was detected only 1 day before, or concomitant with, the onset of signs of EAE. Both, or concomitant with, the onset of signs of EAE. Both the "ear" and "organ" radiometric index tests are useful in measuring the degree of cell-mediated inflammation in EAE, and supplement routine histopathological and observational assessments.
The outcome of pregnancy in chronic active hepatitis (CAH) was studied retrospectively, together with a survival analysis of patients and a comparison of fertility with that expected from controls drawn from the normal Australian population. Clinical records of 73 cases of CAH included 37 women who were potentially fertile (aged 15-45 years) and there were 30 pregnancies among 16 of these women. Hepatic and obstetric complications and the outcome for the foetus and the mother were compared with the results from 36 reports accumulated from the literature. The results showed an incremental increase in survival of patients with CAH according to decade of diagnosis from 1950 and similar severity of liver disease in those who did, or did not, become pregnant. Fertility was reduced in patients with CAH. Relapse of CAH occurred during pregnancy in only two patients, hepatic complications were minimal, and there was no consistent pattern of alteration in liver function; 12 of 16 mothers are alive for a mean period of eight years after pregnancy. Obstetric complications included urinary tract infections (six), toxaemia of pregnancy (nine) and prematurity (seven); of the 30 pregnancies, four were terminated on medical advice in the early years of the study, three ended in spontaneous abortion, and there were four perinatal deaths giving a foetal loss rate of 33 per cent. Despite the maternal disease and use of prednisolone and azathioprine during pregnancy, the single congenital abnormality was pyloric stenosis. We conclude that in CAH fertility is reduced but pregnancies which occur can proceed without detriment to the mother provided that prednisolone treatment is maintained; that a higher than normal foetal loss can be expected; and that babies may be born prematurely but will be normal.
Attempts were made to transmit possible infectious agents from tissue of MS patients into three animal species, under conditions designed to enhance the development of such an agent. Myelination was monitored by measuring CNPase activity and myelin basic protein. Although no significant effects were observed, the usefulness of a new assay for CNPase was demonstrated. Nude mice were found to have a lower level of CNPase than their heterozygous littermates.
Antibody production to the liver-specific F antigen was tested in recombinant strains of mice of different H-2 types to determine whether a histocompatibility-linked immune response (Ir) gene controlled responsiveness to this antigen. Responseiveness was found to be controlled by an Ir gene located in the K end (K and/or I-A subregions) of the H-2 complex.
The adequate care of a patient entails consideration of his social and psychological problems in addition to the relevant medical data. To facilitate this integrated approach, a Social Work Indices Checklist (SWIC) is described, and its use in practice is illustrated. A narrative report is generated from a possible 3095 items of information recorded in SWIC.
The blastogenic transformation of lymphocytes on exposure to antigen was used to investigate cell-mediated immune responses to viruses implicated in the pathogenesis of multiple sclerosis. In 12 patients with "early" multiple sclerosis, lymphocyte reactivity to measles virus, parainfluenza virus, and vaccinia virus did not differ significantly from reactivity in a healthy control group. However, there was a significant inverse correlation between the lymphocyte blastogenic response to measles and vaccinia viruses and the predetermined degree of disability from multiple sclerosis. A deficient cellular response to measles virus, and possibly to other common viruses, is therefore probably a consequence of the disease itself, and not a causal factor.
An 'immunological profile' of various indices of B-cell function and T-cell function was developed for the 'early' case of multiple sclerosis (MS). This was compared against two groups of controls comprising age and sex-matched healthy subjects, and patients with other disabling neurological diseases (CNS controls) who were matched for age, sex, and type and duration of disability. Some indices of humoral immune responsiveness, such as the induced primary response to monomeric flagellin and the 'resting' levels of antibody to measles and rubella viruses, showed significant augmentation. Cellular immune deficits were attributed to an illness effect per se because (a) cell-mediated immunity was depressed, but only when compared with that of healthy subjects and not when compared with that of the CNS controls, and (b) transformation responses of lymphocytes to viral antigens were inversely related to disability status. The abnormalities in humoral immune responses demonstrable in this study do not provide an explanation for this disease; if there is a relevant 'immunological fault', the nature of this needs to be sought from within the neuraxis rather than from the systemic circulation.
A 34 year-old woman with Werner's syndrome has been studied in the light of the current concept that this disorder is a model of premature aging. Endocrine function assays revealed an abnormal glucose tolerance and in vivo insulin insensitivity after prednisolone, and ovarian failure. Immune function assays revealed hypo-responsiveness in skin tests for delayed hypersensitivity, a poorly sustained IgG anti-body response after immunization with flagellin, and a low count of colony-forming T lymphocytes in blood. Cultured fibroblasts had a very limited capacity to replicate in vitro, in comparison with donors of similar age and, moreover, 85% of glucose-6-phosphate dehydrogenase in the patient's cultured fibroblasts was heat-stable at 60 degrees C compared with 100% for a healthy control. Cell receptors (for insulin) were examined by insulin binding to isolated fat-cells, with the finding that fat-cells were abnormally large for the patient's size, and their receptor density was low. The findings from the study point to a genetic defect in Werner's syndrome which, in its effect on particular tissues, may simulate features of aging, but the disease is not a true model of premature aging.
Colony-forming T-lymphocytes were studied in the blood of twenty-two patients with systemic lupus erythematosus (SLE) by the technique of plating phytohaemagglutinin (PHA) stimulated lymphocytes in soft agar. The mean count of T-lymphocyte colonies in SLE of 70+/-64 (1 s.d.)/mm3 of blood was considerably less than the count of 218+/-102/mm3 for healthy young adults and of 139+/-99/mm3 for aged persons. In SLE, counts of T-lymphocyte colonies correlated with low counts of T-lymphocytes in blood and with other indices of T-lymphocyte impairment. The data point to derangement of factors which influence the capacity of T-lymphocytes to proliferate, but it cannot be stated to what degree this is a cause and/or result of the autoimmune disease process associated with SLE. Cloning of peripheral blood T-cells could help determine whether the essential defect in SLE is in the T-lymphocyte or one of its sub-sets, or in factors produced by adherent cells which are essential for growth in vitro of T-lymphocyte colonies.
The secondary antibody response to 5.0 microgram flagellin was studied by haemagglutination in 132 healthy or convalescent subjects given a primary challenge with 5.0 microgram flagellin from 1 to 44 months previously. The peak titre, expressed as total antibody, occurred at 2 weeks and was mainly immunoglobulin (Ig)G. The magnitude of the titre of total antibody was influenced predominantly by that of total antibody in the primary response (P less than 0.001), the interval between primary and secondary responses (P less than 0.005) and the subjects' age (P less than 0.05) and sex (P less than 0.08). Together these accounted for 23% of the variability observed in the secondary response, with total antibody titre in the primary response accounting for 11% of the variability. The titre of IgG antibody was likewise influenced by these four variables, but the influence of age or sex on IgG antibody was not statistically significant. In human vaccination programmes, choice of the appropriate interval between primary and booster inoculations could increase prophylactic effectiveness and, if two inoculations were to prove as effective as three, there would be reduced work and increased public acceptance. Moreover, the demonstrable capacity for responsiveness of aged and debilitated persons should encourage the wider use of appropriate prophylactic immunization in these groups.
A comparison of immune competence in 26 patients with Down syndrome in an institution and 26 matched healthy controls revealed an atypical pattern of T-cell immunodeficiency in the Down-syndrome patients. The patients with Down syndrome had a lymphocytosis in blood with high counts of T (and B) cells, but with impaired effector function of T cells as judged by anergy to dinitrochlorobenzene, low responsiveness to ubiquitous antigens which elicit delayed-type hypersensitivity reactions, and low mitogenic activity of non-stimulated and phytohaemagglutinin-stimulated lymphocytes in culture. Helper-T-cell function measured by the humoral immune response to flagellin was intact, and there were minor abnormalities of the B-cell system. Attempted restoration of T-cell function with levamisole was unsuccessful. This pattern of T-lymphocytosis with impaired effector function could be explained by "stress-deficiency" of the immune system consequent upon a heavy load of infection in early life.
Antigen-induced arthritis was established in the mouse by immunizaiton with methylated bovine serum albumin (mBSA) in complete Freund's adjuvant with B pertusis vaccine. The knee joint was injected after 21 days with mBSA in saline. The arthritis was chronic, antigen-specific, and T-cell dependent in hypothmic nu/nu mice. C57BL and balb/c mice were susceptible, whereas CBA mice were relatively resistant. Susceptibility was dominant; one gene was loosely linked to the "b" allele of the H-2 complex of C57BL mice.
The binding of radioiodinated basic protein of myelin ([125I]BPM) to a sheep lymphocyte cell pellet, sheep erythrocytes, and cell-free tubes used in the assay was investigated as a possible diagnostic procedure in multiple sclerosis. [125I]BPM apparently bound to 5 x 10(6) sheep lymphocytes incrementally with no plateau, up to 300 ng, and also to sheep erythrocytes; when cells were transferred to fresh tubes, over 90% of the radioactivity remained on the original tube, regardless of the tube surface. Various substances, including BPM and unrelated basic proteins, competitively inhibited the binding of basic protein of myelin to sheep cells and assay tubes. Binding was inhibited by sera from patients with multiple sclerosis, but equally so by normal sera. The large capacity of BPM to bind nonspecifically could limit its use in the above type of binding assay and would need to be allowed for in conventional radioimmunoassays.
Interest in immunogenetics originated from two streams: (a) histocompatibility in mouse and man, and (b) inheritance of specific immune responses in the guinea pig and mouse. In the mouse, there are genes associated with the major histocompatibility complex (MHC) which (i) code for antigens determining allograft responses and mixed lymphocyte reactions, (ii) control responses to certain antigens (Ir genes), and (iii) code for cell-surface antigens which elicit specific antisera (anti-Ia). In man, there is genetic control, in part X-linked, over levels of immunoglobulins and immunoglobulin classes. Evidence for MHC-linked genetic control is derived from immune responses to (i) micro-organisms, (ii) pollen antigens, (iii) food antigens, (iv) vaccines, (v) inocuous test antigens, and (vi) autoantigens. Some evidence exists for allotype-linked genetic control. Practical aspects concern influences of the MHC on susceptibility to disease, within individuals and populations.
Described is the experience from a single histocompatibility typing laboratory sampling, firstly, Australian patients with various immunopathic diseases and, secondly, subjects previously classified as "responders" or "non-responders" to various microbial antigens. The diseases considered included chronic active hepatitis (CAH) and various cirrhoses, "thyrogastric" autoimmune diseases, systemic lupus erythematosus (SLE), rheumatoid arthritis, dermatitis herpetiformis (DH) with intestinal villous atrophy, and multiple sclerosis (MS). The immune responses considered included those to flagellin, candidin, mumps, trichophyton, tuberculin and streptococcal enzymes. The HLA specificities particularly associated with disease included B8 (CAH, thyrotoxicosis SLE, DH, and miscellaneous immunopathic diseases) and B7 (thyrotoxicosis, SLE, DH, and MS). The same specificities were present in excess, although not impressively so, among responders to certain of the microbial antigens, i.e. B7 with high responders to flagellin and B8 (and A1) with responders to trichophyton.
This study examines long term "medical" immunosuppression with azathioprine or cyclophosphamide for immunopathic disease in relation to cancer and foetal malformation. The experience represent an aggregate of 241 years of treatment and 508 patient-years of follow-up in 133 non-transplant patients. For azathioprine the mean duration of treatment was 1-9 years and the mean duration of observation was 3-8 years, and for cyclophosphamide, the mean durations of treatment and observation were 0-7 and 4-6 years. A sample of 70 patients was shown by in vivo tests to have significantly suppressed cell-mediated immunity. In the period of review there were observed two cancers, both squamous cell carcinomas of skin, two benign neoplasms and six keratoses; after the period of review, three further cancers were recorded, one being in a subject with a known previous cancer. Nine pregnancies with azathioprine yielded no foetal malformations.
The subject of Clinical Immunology is developing hand in hand with a wide and rapidly moving area of laboratory technology. The result is a better understanding of autoimmune disease, tissue transplantation rejection, foetal-maternal incompatibility, allergic disease, immunodeficiency disorders, adverse reactions to drugs, aberrant responses to bacterial and viral infections, and growth and spread of malignant cells. Basic to this understanding is the need to appreciate the character and composition of natural substances which act as immunogens and elicit antibodies. These substances have, according to their origin, been classified as autoantigens, alloantigens, xenoantigens and neoantigens. This review summarizes our knowledge relating to such antigens, emphasizing those aspects relevant to human disease and pointing to the major gaps that future research must bridge.