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The role of thymic epithelium in T cell development has given rise to a number of studies, but less information is available concerning the factors regulating thymic epithelial cells (TEC) themselves. Several cytokines, natural or recombinant, were investigated for their effects on human TEC proliferation. This study presents evidence for the first time that human recombinant interleukin 1 (IL1) and IL1-containing mixed cytokine preparations induced DNA synthesis of TEC as measured in a 48-hr stimulation assay. The effects of IL1 were dose dependent and sustained in time. The following recombinant cytokines, IL2, IL3, IL4, interferon-gamma (IFN-gamma), IFN-alpha, tumor necrosis factor-alpha (TNF alpha), and TNF beta, as well as thymosin fraction 5 and Escherichia coli lipopolysaccharide (LPS), were not found to modify TEC proliferation but IFN-gamma and TNF alpha enhanced the effects of IL1. We also report that IL1 induced a profound change in the morphology of TEC. Our observations suggest that TEC are targets for the action of cytokines and emphasize the important role played by IL1 within the thymus.

Over the last 23 years, progress in renal transplantation has dramatically decreased mortality and transplant failures, especially during the first years following the transplant. Further improvement in immunosuppression or in induction of specific unresponsiveness should, in the future, limit the incidence of late failures. More experience in transplantation has led to reduced frequency and severity of most complications. This has resulted in acceptance of patients with risk factors such as old age or infancy, poor vascular status, hyperimmunization, or requirement for several transplants (kidney + pancreas, kidney + heart, kidney + liver, etc.). Optimum organ procurement facilities will be required to meet the increased demand for kidney transplants. It is hoped that this need will be stabilized when late transplant failures will become infrequent, thus decreasing the requirements for retransplantation.

The aim of this study was to investigate a possible reenhancement of islet cell autoimmunity in type I (insulin-dependent) diabetic patients who received HLA-mismatched pancreas transplants from cadaveric donors and who underwent generalized immunosuppression. Circulating islet cell antibodies (ICA) and complement-fixing ICAs (CF-ICAs) have been tested at 1, 2, 3, 6, and 12 mo and at least once a year posttransplantation in 23 recipients of 25 transplants (22 simultaneous with kidney, 2 retransplants, 1 isolated; 23 segmental neoprene injected, 2 whole with enteric drainage). Patients were aged 35.3 +/- 1.9 yr with a duration of diabetes of 20.6 +/- 1.1 yr. Immunosuppression consisted of double or triple association of azathioprine, cyclosporin, and prednisone with or without temporary antilymphocyte globulins. The number of HLA-A and HLA-B compatibilities was none in 8 patients, one in 12 patients, two in 4 patients, and three in 1 patient. The mean follow-up was 4.0 +/- 0.4 yr/patient (range 0.4-7.2). ICAs were positive pretransplantation in 2 of 25 patients and reappeared 1-42 mo posttransplantation in another 7. In 6 patients, CF-ICAs were also positive. In 7 of 9 ICA+ patients the pancreas transplant failed; in 1 patient this occurred 4 mo before ICA reappearance, and in 6 patients it occurred 2-35 mo after the first detection of ICAs. Pancreas-transplant failure was significantly associated with the positivity for ICAs (P less than .05) and particularly for CF-ICAs (P less than .005). ICA positivity was transitory in 4 patients (2-27 mo) and persistent in the remaining 5 (up to 61 mo).(ABSTRACT TRUNCATED AT 250 WORDS)

A study was conducted of the circadian hormonal and metabolic patterns of 10 type I (insulin dependent) uraemic diabetic patients after pancreas and renal transplantation. A single 24 hour profile was obtained in each patient following as closely as possible his or her normal daily routine two to 15 months after transplantation. None of the patients were using insulin at the time of the study. Compared with a group of six normal subjects the transplant recipients had mildly raised blood glucose concentrations, hyperinsulinaemia between meals and at night, delayed postprandial insulin peaks, mild hyperketonaemia, and normal blood lactate and plasma glucagon concentrations. The findings showed that successful pancreas transplantation results in disappearance of the need for insulin and return to normal or near normal of the metabolic abnormalities of diabetes. The minor differences observed in comparison with normal hormonal and metabolic homoeostasis were probably due to intrinsic (reduced islet mass, denervation, peripheral hormone delivery) and environmental (immunosuppression, relatively impaired renal function) factors.

Antilymphocyte antibodies can be used to dissect the lymphocyte populations and subpopulations. In the mouse, at least seven gene loci govern the expression of allo-, hetero-and autoantigens at the surface of T-lymphocytes. The antisera, especially the alloantisera, permit definition of the differentiative state of cells and discriminate between subsets of T-cells with different functions. Less is known about human T-lymphocyte differentiation antigens and their genetic determinism. However, heterologous antisera specific for human T-cells have been prepared and their use has been of help in studying this cell population. The antigens recognized by such antisera are present at a higher concentration on thymocytes than on peripheral blood T-lymphocytes. They appear at the surface of bone marrow T-cell precursors after a short incubation with thymic factors. Such markers of T-lymphocytes in various stages of differentiation and the study of in vitro differentiation from precursor cells have already proven to be valuable tools for clinical investigation, especially in the realm of immunodeficiency diseases.

Parathormone levels were determined in 17 patients with functioning renal transplants. In 8 patients recently transplanted, very high serum levels of parathormone were found without obvious relation to the glomerular filtration rate. Hypophosphatemia was also present in these cases. In 9 other patients studied 2-7 years after transplantation the mean level of parathormone was lower than in the previous group but levels above normal were noted in half of the patients, some of which had perfect renal function and normal serum phosphorus. The response to induced hypercalcemia was used as a sensitive test to reveal abnormal responses even in cases which initially had normal peripheral levels of parathormone. From these results, tertiary hyperparathyroidism would appear to be rare although hyperfunctioning parathyroid glands can be demonstrated long after kidney transplantation, even when renal function is close to normal.

A small renal cell carcinoma was transplanted inadvertently with a kidney from a living donor and was treated with partial nephrectomy. Secondarily, tuberculosis of the renal allograft appeared, which was followed by nephrolithiasis. The kidney was left in place, immunosuppressive treatment was continued and renal function is normal more than 8 years after transplantation, with no sign of the cancer progressing or reactivation of the tuberculosis.

An infant with a family history suggestive of immunodeficiency presented with combined immunodeficiency. No HLA-A and -B antigens were present on lymphocyte and platelet surfaces, but they were found in the serum. HLA-D determinants were present on lymphocytes. In spite of a fetal thymus transplantation, the infant died of infections associated with the immunodeficiency. The thymus and lymphoid organs were present but hypoplastic and contained few lymphocytes at postmortem examination. The finding of an immodeficiency associated with an absence of cell-surface HLA-A and -B antigens may be regarded as the consequence of the lack of cellular histocompatibility antigens on immune development. Alternatively, other membrane components may have also been defective and partly responsible for the observed abnormalities.

Induction of thymus-dependent lymphocyte (T cell) differentiation was performed in vitro with thymic factors as inducers. T cell precursors from human bone marrow first expressed surface differentiation antigens and then acquired the capacity to form rosettes with sheep erythrocytes. The latter marker could not be induced when cells with differentiation antigens had been eliminated. The proliferative responses to phytomitogens or to allogeneic stimuli appeared to be characteristics of later stages in differentiation that also can be induced or amplified by in vitro incubation of marrow cells or thymocytes with thymic factors. When phytomitogen-responsive cells from peripheral blood were inactivated in vitro, the allogeneic response was enhanced. Although these responses are acquired almost concomitantly, they are therefore envisioned to be characteristics of separate T cell subsets. After immunological reconstitution of patients, the T cell development in vivo involves a succession of differentiation events similar to that described above. Our experiments with mice, using similar methods, have also shown that graft-versus-host inducing capacity is a function of a cell population distinct from that which yields a proliferative response to in vitro stimulation by phytohemagglutinin. These results support our model of sequential differentiation of human prothymocytes into various subsets of mature T cells.

Immunostimulants have large potentialities but their clinical evaluation and development are still in infancy. The appropriate time to start clinical studies is not always easy to determine: when some knowledge is available on the targets of the molecule and on assays demonstrating some immunological effects, but before a full elucidation of the precise mechanism of action. The clinical fields in which an immunomodulator can be analyzed are very large: immunodeficiencies, infectious diseases, auto-immune conditions, allergic diseases etc., provided that there is a target cell able to respond to the compound. Well-controlled, double-blind investigations are necessary, using objective clinical criteria and precise laboratory tests. Adverse effects, including bone marrow lesions or auto-immune manifestations, should be carefully looked for. The presently described strategy will probably be modified with progresses in this new discipline. A precise methodology for clinical evaluation will hopefully contribute to the development of more and more potent immunomodulators with a clearly defined activity in human diseases.

We studied natural killer (NK) cell activity and numbers in the peripheral blood obtained from patients with Behçet's disease (BD) in inactive and convalescent stage, and from healthy controls. Ratios of helper/suppressor cells (OKT4/OKT8) were below 1.0 in patients with active stage and were normal in the convalescent stage of BD. A relative increase of OKT8+ cells and at the same time of Leu 7+ cells was obtained in the active and convalescent BD stages. Double marker analysis revealed that the sub-population of cells expressing both the T8+ and the Leu 7+ antigen (T8+/Leu 7+) was increased in patients with active stage, and normal in the convalescent stage. The frequency of cells reactive with Leu 11 monoclonal antibody (active NK cells) was evaluated in patients with BD. Data from peripheral blood showed an increased sub-population of T8+/Leu 7+ double marker cells, and a decreased Leu 11+ cell sub-population in patients with active BD, but the majority of Leu 7+ cells in patients with convalescent stage lacked OKT8 antigen when investigated in a double marker system. A parallel increase of Leu 11+ cells was observed in the convalescent stage. This phenotypic analysis was carried out with the NK in vitro functional evaluation of cell populations from peripheral blood. NK cell activity in the clinically active stage of BD was significantly lower than that of healthy controls and patients in the convalescent stage. The decrease of peripheral blood NK function in patients with active BD may be related to the presence of immature forms of NK cells and/or to the increased percentage of T8+/Leu 7+ cells.

Mouse serum collected 24 hr after administration of sodium diethyldithiocarbamate was shown to convert a subset of null cells, not bearing the human T lymphocyte differentiating antigen (HTLA cells) into HTLA+ cells in man. In addition to inducing surface characteristics of T lymphocytes, the serum of treated mice increased functional activities of human peripheral blood lymphocytes, including the response to Con A and the suppressor activity in vitro.

An improved purification method for isolating an immunosuppressive fraction from uremic ultrafiltrates was described. Lyophilized ultrafiltrates were fractionated on Sephadex G-15 and the active fraction was further purified using high-performance liquid chromatography. The inhibitory effect of eluates on in vitro lymphocyte proliferation was assessed at the different steps of purification. Results obtained after enzyme treatment suggested that the substance(s) responsible for the immunosuppressive activity is (are) of peptidic nature. This peptide appears to be different from the other peptides previously reported, which have a much lesser activity in the lymphocyte proliferation assay.

An antiglobulin assay, derived from the indirect Coombs' reaction has been adapted to the titration of antilymphocyte globulin (ALG). Ten different ALG preparations have been investigated by this test and titres obtained are satisfactorily correlated with skin allograft survival in monkeys, rosette inhibition and mixed lymphocyte reaction inhibition. The antiglobulin test has also proved to be valuable for the monitoring of ALG-therapy in patients as well as for studying the mode of action of this potent immunosuppressive agent.