HLA, islet cell antibodies, and types of diabetes mellitus.

Insulin-dependent diabetes mellitus, in contrast to non-insulin-dependent diabetes mellitus, is associated with HLA factors B8, BW15, and B18. Recent studies have shown the association to be even stronger with HLA, DW3, and DW4 and have produced evidence for the existence of two "diabetogenic" genes predisposing to insulin-dependent diabetes in different ways. Evidence to suggest the existence of a gene--associated with DW2--that protects against the disease is accumulating. Islet cell antibodies are a feature of insulin-dependent diabetes mellitus and can be seen, in most cases, at the time of diagnosis.

Studies of the HLA system and insulin-dependent diabetes mellitus.

The relationship between the HLA system and insulin-dependent diabetes mellitus (IDDM) is reviewed. Data compiled by the HLA and Disease Registry reveal that HLA-B8 and/or Dw3 are associated with IDDM in all populations studied so far, but further population studies in non-Caucasian populations should be performed. In Caucasians, HLA-Dw2 renders protection against IDDM while HLA-Dw3 and Dw4 are associated with susceptibility to IDDM. The exact mode of inheritance of susceptibility to IDDM remains to be established. Involvement of at least two genes is likely. Heterogeneity of IDDM is highly possible and should be a matter of major interest in diabetes research.

T-cell subset alterations and lymphocyte responsiveness to mitogens and antigen during severe primary infection with HIV: a case series of seven consecutive HIV seroconverters.

Seven consecutive patients who presented with a severe acute mononucleosis-like illness associated with HIV seroconversion were evaluated by T-cell subset enumerations and measurements of lymphocyte transformation responses to mitogens and antigen during both their primary illness and a 1-year follow-up period. We observed a characteristic pattern of response to primary HIV infection; initial lymphopenia was followed by CD8 lymphocytosis and inversion of the CD4:CD8 ratio. During follow-up, the CD8 count gradually returned to normal, whereas the CD4:CD8 ratio remained inverted because of a relatively low number of CD4 lymphocytes. Primary infection was followed by prolonged and severe cellular hyporesponsiveness to both mitogens and antigen. At the last follow-up, responses to pokeweed mitogen were still severely impaired, with a median 19% (range 7-50%) of that observed in healthy controls. We conclude that severe primary HIV infection may be followed by sustained lymphocyte hyporesponsiveness, a sustained low percentage of CD4 lymphocytes and sustained inversion of the CD4:CD8 ratio.

Catecholamine metabolism during heroin use.

The authors examined urinary levels of catecholamines and metabolites during a 10-day period of heroin use in 9 subjects. Catecholamine and metabolite excretion increased over baseline values on the first day of heroin use, but markedly different patterns of change emerged later. In contrast to the significant increase in normetanephrine and decrease in metanephrine excretion in all 9 subjects during heroin use, only 4 subjects showed an increase in 3-methoxy-4-hydroxyphenyl glycol (MHPG) excretion. Moreover, it appeared that the increase in MHPG excretion in this subgroup began on the day before heroin administration, which suggests the possibility of an anticipatory or conditioned response.

HLA and heterogeneity of multiple sclerosis.

Age at onset, debut symptoms, optic nerve signs, and severity of symptoms were evaluated from the medical records of 135 patients with MS. HLA-D/DR2 was significantly more frequent in rapidly progressive MS, and D/DR2 seemed to confer both susceptibility to the disease and to more rapid progression. However, D/DR3 seemed to protect against rapid progression.

The impact of low donor-specific MLR versus HLA-DR compatibility on kidney graft survival.

We have analyzed the predictive value on cadaver kidney graft survival of a low stabilized relative response (SRR) in donor-specific mixed lymphocyte culture (MLC). Thirty-eight recipients and donors of cadaver kidneys constituted the case material. The 12-month survival of cadaveric grafts was 83% when the SRR values of the mixed lymphocyte reaction (MLR) between recipient and donor were below or equal to 50 and 40% when the SRR values were above 50. The difference was statistically significant (P less than 0.006). A higher (though not significantly so) graft survival rate was obtained in transplant groups when the recipients and donors were well matched for DR antigens. The 12-month survival was 70% when no DR incompatibilities could be demonstrated and 50% when one or more DR antigens were incompatible. The primary role of MLR matching for the outcome of kidney graft survival is supported by the observation that the influence of the MLR is still significant when stratified for DR matching (P less than 0.05). In conclusion, when adequately stabilized, the specific MLC reactivity of the recipient against the donor is a very important predictive factor for the outcome of cadaver kidney transplantation, which stresses the importance of improvements in serological DR typing.

Successful nonsibling bone marrow transplantation in severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) was diagnosed in a girl immediately after birth; her older brother had SCID and was successfully reconstituted by bone marrow transplantation from his uncle. She was isolated in a laminar air flow bench and decontaminated. The father differed by one HLA-A antigen but was HLA-Dw2 homozygous like the patient; his lymphocytes showed a slight response to the patient's cells in mixed lymphocyte culture (MLC). At the age of 2 1/2 months and again at 5 months, she was given a bone marrow transplant from the father. During the entire course the patient had no infections, and apart from a transient eosinophilia she had no signs of graft-versus-host reaction. Immunological reconstitution was nearly complete at 9 months of age, when she was recontaminated. One year later plasma immunoglobulin concentrations are in the low normal range (IgG and IgM) or decreased (IgA); tests of cell-mediated immunity are normal. Apart from slight upper respiratory infections, the patient has been healthy. Physical and psychological development have been normal.

Typing for human alloantigens with the primed lymphocyte typing (PLT) technique with notes on the interpretation of PLT data.

A typing system for HLA-D/DR-associated PLT-defined determinants, which have been called "DP" antigens, is reported. Some of the results concerning a data interpretation system, the reproducibility of PLT results, and the correlations between the results of HLA-D, -DR, and DP typing are presented. Also, a "new" human alloantigen, EP1, not belonging to the series of DP antigens, is defined with PLT.

Alloactivated HLA class II-positive T-cell lines induce IL-2 reactivity but lack accessory cell function in mixed leukocyte culture.

Recently, much interest has focused on the role of HLA class II antigens in T cell-T cell interactions. We have studied the stimulatory capability in the primary mixed leukocyte reaction and the primed lymphocyte reaction of 11 alloactivated, HLA-DR- or -DP-reactive CD4-positive T-cell lines (Ta). From 70 to 90% of the Ta were HLA class II-positive as judged by the reactions with HLA class II-reactive monoclonal antibodies, and the Ta carried the DR allospecificities of the original T-cell donor when typed in the microcytotoxic test using DR-specific alloantisera. Neither irradiated nor nonirradiated Ta stimulated primed lymphocytes directed against the relevant HLA class II antigens on the Ta. Interferon-gamma, recombinant interleukin 1, phorbol myristate acetate, calcium ionophore, and adherent cells had no effect on the stimulatory capability of Ta. The ability of irradiated Ta to stimulate in the primary mixed leukocyte reaction (median counts per minute (cpm) 5.5 x 10(3] was significantly lower than that of peripheral blood mononuclear cells (cpm: 44.0 x 10(3]. The stimulation by Ta was almost only seen when the Ta were specifically directed against the class II antigens of the responder peripheral blood mononuclear cells (i.e., in combinations with "backstimulation") (median cpm: 21,000). In mixed leukocyte reaction combinations without backstimulation, significantly weaker reactions were seen (median cpm: 1,000). This observation may explain previous controversies concerning the stimulatory capacity of Ta. Recombinant interleukin 2 significantly enhanced the very low mixed leukocyte culture responses induced by class II-incompatible Ta in combinations without backstimulation but had no significant effect on cultures with Ta autologous to the responder peripheral blood mononuclear cells. Thus, allogeneic class II-positive Ta can induce interleukin 2 responsiveness but lack accessory cell function(s) necessary for the induction of interleukin 2 production in primed and unprimed T cells.

Defective T-cell stimulatory pathways in patients after allogeneic bone marrow transplantation (BMT) in man.

Immunological reconstitution after allogeneic bone marrow transplantation in man is characterized by a decreased lymphocyte transformation response to various mitogens and antigens during a period of from months to years. One reason for the decreased proliferative capability could be an inverted CD4/CD8 ratio; however, the present investigation demonstrates that this is not the only explanation for the immunodeficiency, since the CD4 as well as the CD8 subset, when studied in isolation, have qualitative defects, as evidenced by a reduced response of both subsets to stimulation with PHA, anti-CD2 and anti-CD3 MABs. The reason for the qualitative defect is unknown but a distorted composition of the CD4+ as well as the CD8+ T-cell subsets is suggested by the present investigations. We also observed that the PHA response was almost completely reconstituted one year after BMT, while the PWM response was still severely affected. The present study suggests that T-cell subsets which differ in their capacity to respond to PHA and PWM have different kinetics of reconstitution after BMT.

The effects of tranylcypromine isomers on norepinephrine-H3 metabolism in rat brain.

The effects of d- and l-tranylcypromine on the disposition and metabolism of intracisternally administered l-norepinephrine-H3 were studied in rat brain. Both isomers inhibited the deamination of norepinephrine-H3. However, d-tranylcypromine was considerably more potent than the l-isomer in this respect. In addition, the l-isomer of tranylcypromine was found to enhance the disappearance of endogenous and tritiated norepinephrine from brain. Although this action appeared to result from an increase in catecholamine release, the possibility of uptake inhibition could not be eliminated. The l-isomer of tranylcypromine enhanced the disappearance of norepinephrine-H3 from brain when administered both 20 and 90 min following intracisternal injection of the label. Comparable doses of d-tranylcypromine did not exhibit this effect. Larger increases in brain levels of normetanephrine-H3 were produced by d,l-tranylcypromine than by either the d- or l-isomer alone, indicating that the racemic mixture may produce the greatest increase in the interaction of norepinephrine with its postsynaptic receptors.

Opiates, catecholamines, behavior, and mood.

Indirect evidence has linked opioid reinforcement with changes in noradrenergic metabolism secondary to drug administration. Methodological precedents for biobehavioral correlations in depressive illness have suggested an important association between changes in mood and biogenic amine excretion patterns in the urines of patients during depression and recovery. This paper presents preliminary data on the possible relationship between changes in catecholamine excretion that were observed and the changes in behavior, mood, psychiatric status, and cardiorespiratory physiology secondary to heroin administration and methadone-assisted withdrawal. This study focuses on the urinary excretion of MHPG, since an appreciable fraction of this metabolite is probably derived from norepinephrine originating in the brain. The subjective changes in mood associated with heroin use, the decrease in respiratory rate, and the behavioral and mental status effects associated with opiate intoxication were observed only in the individuals whose MHPG excretion increased during the period of opiate administration.

Novel primary thymic defect with T lymphocytes expressing gamma delta T cell receptor.

Flow cytometric analysis of the peripheral blood mononuclear cells in a six year old girl with a primary cellular immune deficiency showed a normal fraction of CD3 positive T cells. Most (70%) of the CD3 positive cells, however, expressed the gamma delta and not the alpha beta T cell receptor. Immunoprecipitation and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) showed that most of the gamma delta T cell receptors existed as disulphide-linked heterodimers. Proliferative responses to mitogens were severely reduced, but specific antibody responses after vaccination could be detected. A thymic biopsy specimen showed severe abnormalities of both the thymic lymphoid and epithelial component with abortive medullary differentiation and almost an entire lack of Hassall's corpuscles. This patient represents a case of primary immune deficiency syndrome not previously described. Thymic deficiency associated with a high proportion of T cells expressing the gamma delta T cell receptor has been described in nude mice, and it is suggested that the immune deficiency of this patient may represent a human analogue.

HLA (SD and LD) in patients with amyotrophic lateral sclerosis (ALS).

Twenty-five patients with a definite diagnosis of amyotrophic lateral sclerosis (ALS) were HLA-typed for the serologically detectable antigens A, B and C and MLC-typed for 7 HLA-D-determinants. No significant deviation was found neither in the A, B, and C-series nor in the HLA-D-series as compared to normal controls. The aetiological problem of ALS is discussed.

HLA studies in diabetics.

The studies of HLA in diabetes mellitus have strongly supported the subdivision into (at least) two genetically distinct groups: The juvenile onset (or perhaps better the insulin dependent) type DM, which shows a marked association to the HLA system, and the maturity onset type with a weak or no association to HLA. The HLA system has provided tools to test specific genetic models for the insulin dependent DM. A model involving one disease susceptibility locus closely linked to the HLA-loci and with a recessive susceptibility allele in linkage disequilibrium with some of the HLA factors has been proposed by others. This model cannot be totally rejected on the basis of the available data, but it is made less likely, especially because it leads to very low estimates of the penetrance which is discrepant from independent estimates, based both on studies on monozygotic twins and other families. In addition suggestive but not yet conclusive evidence of an excessive risk for HLA-Dw3/Dw4 heterozygotes is in conflict with this model.

An unusual case of multiple malignancy in an adult.

An adult female is described who, during a clinical course of 25 years, presented malignant tumors of the rectum, breast, uterus and colon. Cytostatics were never administered. Lymphocyte subsets, a variety of lymphocyte and mononuclear cell stimulation assays with mitogens and antigens, DNA repair tests and activity of natural killer cells were normal. Serum leukocytic interleukin-1 activity was slightly elevated. Sister chromatid exchange frequency in peripheral lymphocytes was below the normal range. An explanation for the development of 4 primary malignant neoplasms was not found.

HLA-DR typing in cadaver kidney donors and recipients in Copenhagen.

Among 224 cadaver kidney transplantations performed since Spring 1977, successful DR typing of both donor and recipient could be done in 149 cases. Assessment of DR match grade and clinical data was done independently. The minimum observation time was 3 months and the time of follow up was 1 December, 1980. There was an effect of DR matching which became significant when only 1. transplants were considered and high risk recipients (i.e. diabetics) excluded. Transfusions were of minor importance on graft survival and the difference was only obvious in the first year after transplantation. Matching for HLA-A, B antigen had no obvious effect on graft survival in this material.