Search

The excellent results of Transplantation over the last decades have highlighted new challenges to be solved in the next years. (1) Modify the storage of harvested organs to improve their quality. (2) Modify strategies by taking into account the immunodeficiency in front of news infections like the one with Sars CoV-2. (3) Better understand the mechanisms of chronic rejection, in particular the role of innate immunity. (4) Rethink immunosuppressive strategies to prevent and to treat chronic rejections.

The results provide new insights into the role of IL-2/IL-2R pathway in DC. We report that stimulation of human monocyte-derived DC with LPS strongly upregulated CD25 (α chain of the IL-2R) expression. In addition, by using a humanized monoclonal antibody against CD25, we demonstrated that the IL-2 signalling in DC upregulated both IL-12 and γIFN production but decreased IL-10 synthesis. Anti-CD25 treatment reduced the ability of LPS-DC to induce allogeneic CD4(+) T cell proliferation as compared to LPS-matured DC. In addition, LPS-matured DC treated with IL-2 had a higher allostimulatory capacity compared to LPS-DC. We also found that LPS-matured DC produced IL-2. Thus, IL-2 seems to contribute actively to DC activation through an autocrine pathway. Moreover, IL-2 pathway in DC is involved in T helper priming. These findings might be useful for protocols in cellular therapy and a valuable tool to understand graft rejection versus the acquisition of peripheral tolerance.

The diagnosis of the pulmonary forms of Goodpasture's syndrome is not easy and requires a renal biopsy when no anti-glomerular basement membrane antibodies are detected, since the disease can lead to spontaneous massive intra-alveolar haemorrhage that can be fatal. Treatment for the pulmonary-renal form combining corticosteroids, cyclophosphamide and plasmapheresis should be applied to the pulmonary form to control haemorrhage and prevent relapse.We report the case of a patient suffering from the localised pulmonary form of Goodpasture's syndrome in whom the diagnosis was delayed due to a negative indirect immunofluorescent antibody bioassay. After a serious early relapse remission was achieved with comprehensive treatment and a tobacco withdrawal programme.If there is no delay in diagnosis and comprehensive treatment is given, the prognosis for these patients is good with a recovery rate of 80 to 90%.

Cyclosporine is an immunosuppressive treatment whose side effects limit its usefulness. Among neurological side effects, neuropathies or myopathies have been reported, specially inpatients given combinations of cyclosporine with co-enzyme A reductase inhibitors.We report here the case of a 67-year-old woman who developed few months after a kidney graft sensorimotor disorders which progressed rapidly. Since all etiologies of such a disorder were ruled out, the hypothesis of toxicity exclusively induced by cyclosporine was suggested and confirmed by the improvement observed after its withdrawal.This observation highlights the fact that cyclosporine may induce neuromyopathies even when given alone at the therapeutic dosage.

FUNCTIONS OF THE ENDOTHELIUM: The endothelium plays a pivotal role in regulating vasomotor tone, vessel permeability, blood cell extravasation, and antiatherogenic, antithrombogenic and antiadhesive processes.Demonstrated, in particular, by endothelium-dependent vasomotricity disorders, endothelium dysfunction occurs in many psysiological and pathological situations that lead to atherosclerosis: advanced age, menopause, high blood pressure, dyslipidemia, diabetes, smoking, elevated homocysteinemia, chronic renal failure.... These dysfunctions of the endothelium constitute the fundamental and very early step in the development of atherosclerosis.Specific treatment of functional anomalies of the endothelium can be an essential element in the prevention of atherosclerosis. In certain cases, he cause of endothelial dysfunction may be related to the presence of radical oxygen species, nitric oxide inhibitors, or increased synthesis or release of endothelin. Potential treatments should be adapted to the specific cause of the underlying endothelial anomaly: antioxidants, statins, anti-endothelins, or converting enzyme inhibitors. In clinical practice, it may be important to recognize the cause of endothelial dysfunction for adapted early drug therapy.

The transplantation of organs from one species to another introduces a question of compatibility not seen in allotransplantation, the ability of a kidney to perform its physiological function in the new host environment. It has been assumed that an allotransplanted organ will function normally if is not rejected; ample experience supports this assumption. This luxury will not exist in the field of xenotransplantation, where the issues of comparative physiology will assume great importance. From many standpoints, the pig kidney seems an ideal donor for xenotransplantation. They are of similar size and have remarkably similar internal anatomy. Even if the immunological problems could be overcome, there is almost no direct experimental evidence to answer the question of whether or not a pig kidney can function in a human body.

We assessed the long-term (M +/- SE: 68 +/- 3 months) arterial pressure and renal function of cadaveric kidney transplant recipients with and without significant (70% diameter reduction) transplant renal artery stenosis (TRAS) at angiography. Baseline clinical, immunological and outcome data for 26 patients with TRAS (incidence of TRAS: 6.6%) before and following angioplasty and 72 patients without stenosis at angiography were reviewed and analyzed. The 2 groups were similar with respect to recipient sex ratio and age (45 vs 46), duration of transplantation (7 months), cause of renal failure, donor sex and age, HLA-antigen mismatches and titers of anti-HLA antibodies, CMV infection and anti-CMV antibodies in donors and recipients. The technical success of angioplasty was 92.3%. Restenosis was documented in 6/26 patients (23.1%). Revascularization resulted in a decrease of arterial pressure and number of antihypertensive medications and a lower serum creatinine compared to baseline values. The long-term arterial pressure and serum creatinine levels were similar in patients with and without stenosis. In conclusion, TRAS after revascularization had no detectable influence on the long-term arterial pressure control and renal function within a follow-up period of 68 +/- 3 months.

Vascular endothelium controls leukocyte recirculation and recruitment, receiving messages from underlying tissues and transforming them into informations quickly read by the passaging leukocytes. These messages induce adhesive interactions between leukocytes and endothelium via adhesion molecules. Multiple receptor-ligand pairs function in 4 steps: initial tethering and rolling of leukocytes; leukocyte triggering by chemotactic factors; arrest and strong adhesion to endothelium; and ultimately transendothelial migration (diapedesis).

The economic impact resulting from the clinical consequences of immunosuppressive strategy using mycophenolate mofetil in new renal transplant recipients was conducted considering the viewpoint of the health insurance system.The analysis was based on the results of three controlled randomized double-blind clinical trials comparing mycophenolate mofetil with placebo or azathioprine in 1003 out of 1493 included patients respectively. Health care costs associated with each event were determined by 7 French experts in renal transplantation working in six different hospitals. Direct cumulative costs for each strategy were compared.The studies demonstrated a difference in the incidence of acute rejection and treatment failures whatever the cause. The three trials showed that, compared with current strategies, use of mycophynolate mofetil in the immunosuppression protocol generated a 19 to 38% cost reduction during the 6 months after transplantation. Cost reduction resulted from lower incidence of acute rejection and the subsequent nephrectomics and dialysis sessions. The sensitivity analysis on the most important cost factors-cost of hospitalization per day and number of hospitalization days-confirmed strength of the results.Use of mycophenolate mofetil in the immunosuppressive prophylaxis protocol after renal transplantation allows a reduction in the direct costs during the 6 months following transplantation.

Cardiac abnormalities, such as myocarditis, pericarditis or verrucous endocarditis (Libman-Sacks endocarditis) occur in about one third of patients with systemic lupus erythematosus. This study describes an unusual aspect of endocardial involvement.Case no. 1: A 14 year-old girl was admitted 3 months after acute hemichorea because of heart failure plus biological inflammatory findings. Echocardiography showed mitral insufficiency with enlargement of the left atrium and ventricle. There was some infiltration involving the endocardium of the left ventricle, the chordae tendinae and the mitral valve. The titres of anti-DNA and anti-nuclear antibodies were elevated while the serum hemolytic complement was depressed. Skin biopsy showed IgG, IgM and C1q deposits along the dermoepidermal junction. Corticosteroids, diuretics and vasodilator drugs failed to completely cure the heart failure; the mitral insufficiency required mitral valve replacement 21 months later. Pathological examination showed extended fibrotic changes of the endocardium. Case no. 2: A 4 year-old boy was admitted for acute heart failure due to mitral insufficiency, associated with biological inflammatory findings. Echocardiography showed mitral insufficiency and enlarged left atrium and ventricle. Anti-DNA and anti-nuclear antibody titres were elevated. The patient was given antibiotics followed by corticosteroids and immunosuppressive drugs. The persistence of the mitral insufficiency required mitral valve replacement 7 months later. Pathological examination showed fibrotic changes of the endocardium. Exacerbation of the inflammatory process was seen 2 months after surgery, with development of diffuse proliferative lupus nephritis. The patient died of kidney failure and neurological complications, 44 months after cardiac surgery.In both patients, the systemic lupus erythematosus was revealed by endocardial involvement, a complication that is usually seen later. The endocardium changes responsible for mitral insufficiency and requiring valve replacement in these two cases were different from those described as verrucous endocarditis in classical forms of the disease.

Lymphocyte adhesion to allogeneic endothelium is a critical step in graft rejection. To further characterize the expression and the regulation of adhesion molecules involved in this process, we stimulated endothelial cells with Interleukin 4 or tumor necrosis factor alpha (TNF alpha) and blocked lymphocyte adhesion to stimulated-endothelial cells with monoclonal antibodies. We demonstrated that lymphocytes bound endothelial cells by at least four adhesion pathways: a) a LFA 1/ICAM 1 dependent pathway on TNF alpha-stimulated endothelial cells, b) a LFA 1 dependent/ICAM 1 independent pathway on unstimulated or IL 4-stimulated endothelial cells, c) a VLA 4/VCAM 1 dependent pathway on unstimulated and stimulated-endothelial cells, d) a CD 2 dependent/LFA 3 independent pathway on IL 4 and TNF alpha-stimulated endothelial cells.

Interleukin 4 and tumor necrosis factor alpha increase endothelial cell adhesiveness for lymphocytes by promoting adhesion molecules synthesis. We have shown that intracellular mechanisms, which transduce IL 4--but not TNF alpha--signal, involve a protein kinase A.

Ultrasound techniques and radionuclide studies are very often used to assess vascularization of renal transplants. Although, in acute tubular necrosis or acute rejection, it is difficult to choose between these two techniques, in 3 recent cases of renal artery thrombosis, we conclude that color coded Doppler is preferable to nuclear medicine or duplex system to diagnose this form of thrombosis.

The aims of the study were the correlation between dosage and plasmatic levels of slow release theophylline and the reason for dosage adjustment. 64 pharmacokinetic studies were performed in 58 asthmatic children between 17 months and 16 years. Plasmatic levels of theophylline were performed by fluoroimmunology technique at H0 (before the dose) 2 (H2), 4 (H4), 6 (H6) and 8 (H8) hours after the dose of slow release theophylline. The best correlation between dose and plasmatic levels were observed at H4 and H6 for Armophylline and Euphylline respectively. Dosage adjustment were based both upon clinical state and plasmatic levels in 55 cases. In 9 cases the modification of dose were decided only because of plasmatic levels out the therapeutic range. The authors proposed a schema of dosage modifications based upon clinical state; plasmatic levels must be used as a guide for dose adjustment in patients clinically uncontrolled.

The progress in organ transplantation is leading an increase in the demand for organs. Any non-harvested organs from a dead child mean at least a delay or even the loss of hope for life. All brain dead children do not undergo organ harvesting because there are still obstacles. The definition of brain death must be clear and include the destruction of all the brain system. Intensive care units must be motivated by improved contacts with transplantation teams. The number of parents who refuse could decrease with better public information, good contacts with medical teams and the quality of discussion with parents when a child dies. Energy should be concentrated on improving the collective consciousness about this new aspect of medicine.

Autoantibodies to the cytoplasmic components of neutrophil polymorphonuclear granulocytes (ACPA) were searched for by indirect immunofluorescence on ethanol-fixed smears from normal white blood cells in 248 sera from patients with Wegener's granulomatosis, Kawasaki disease and various other vasculitides, connective tissue diseases, nephropathies and infiltrative pulmonary diseases. Apart from a weak positivity in a few Kawasaki disease sera, ACPA were found in Wegener's granulomatosis (and micropolyarteritis) only, with a correlation between ACPA titers and disease activity. These results confirm the value of ACPA in the diagnosis and evaluation of activity of Wegener's granulomatosis.

The communication between right pulmonary artery and left atrium is a very uncommon cause of right to left shunt. The 18th case in the world literature and the first case in France is reported here. Normal pressure in the right cavities and in pulmonary artery is evocative. Angiography assesses the diagnosis and precises the place and connections of the fistula. Surgical closing of the fistula must be promptly achieved in order to obviate embolic complications.

Three children out of a total of 40 who had been treated with chlorambucil for juvenile rheumatoid arthritis developed acute leukaemia. No malignancy was detected in 160 patients in those treated with steroids and/or other anti-inflammatory drugs. Chlorambucil may have induced the malignancies and its use should be avoided in rheumatoid arthritis.

Three children with a Bartter's syndrome have been investigated: all of them had growth retardation, hypokalemia (less than 3 mmol/l), raised plasma renin activity and urinary prostaglandins (PGE2 and PGF2 alpha) and a decreased sensibility for angiotensin. In the siblings two children had also growth retardation with mild biological signs of Bartter's syndrome, and two children had normal growth slight hypokalemia raised RPA and urinary PH, and normal sensibility for angiotensin. These data suggest mild forms of this syndrome which could be the Bartter's syndrome diagnosed in adults after laxatives or diuretics absorption. Besides these data stated a negative correlation (p less than 0,01) between plasma K+ and RPA, negative correlation (p less than 0,01) between plasma K+ and urinary PGE2 and a positive correlation (p less than 0,01) between RPA and urinary PGE2. From these observations physiopathology of Bartter's syndrome is discussed.

Improved results of organs transplantation have resulted in an increased request for organs. All brain-dead children do not undergo organ harvesting for 3 main reasons. First, the definition of brain death, which should remain strict, is not accepted by everyone, in spite of the laws on this topics. Then, organizing organs harvesting requires specific hospital structures, a co-ordinator and motivated medical staff. Finally, parent's authorization is mandatory before organs harvesting in children. Parents still often refuse. An improvement might be reached by informing the general public, a maintained trust in the medical profession and the quality of the talk with the parents when the child dies. All energies should tend to develop the collective consciousness in order to improve this new aspect of medicine.

The first patient suffered from a very severe atopic dermatitis with intense pruritus and thickened skin. He had also recurrent infections, particularly related to Staphylococcus coagulase +, and axillary and inguinal lymphodermopathy. The use of tetracosactide given intramuscularly allowed controlling the evolution of his atopic dermatitis. After several months of treatment, the skin became less infiltrated, lymphodermopathy disappeared and no severe infection had happened. The second patient had a less severe atopic dermatitis and recurrent infections without any particular severity. Topical corticosteroids allowed to control the atopic dermatitis. These two patients had high levels of circulating IgE and an important deficiency of polymorphonuclear chemotaxis which was evaluated by migration through boyden room. Study of the family showed atopic manifestations in several members, but with lower levels of IgE. The most characteristic abnormality of this syndrome is the according to considerable increase of IgE. The deficit in polymorphonuclear chemotaxis may vary according to time and even become normal. The prognosis over long periods remains to be determined.

The authors describe a new observation of a congenital aerobiliar fistula in a newborn infant showing choleptysies associated with a pulmonary obstruction. The most remarkable facts are the presence of a radiological pneumogallbladder, and the existence of a real trifurcation of the trachea on the bronchography, associated with a choledocal hypoplasia. The death having occured before the operation, the autopsy allowed the confirmation of the termination on the left hepatical duct and the duality of conformation of the fistula, respiratory and biliary. On the occurence of this 9th case, a review of the literature shows the stereotyped nature of the clinical signs and the course of the fistula which seems invariable. The different aspects of the malformation are considered as well as the treatment which necessitates an exeresis by thoracic pathway.

Thirty French children (18 males, 12 females; mean age 20 +/- 18 months) presenting with Kawasaki disease were treated with high-dose intravenous plasmin-modified immunoglobulins (Veinoglobulines Institut Mérieux, France) during the acute phase of the disease. The total dose ranged from 1 to 2.5 g/kg (mean 1.88 +/- 0.50) administered in 1 to 5 infusions. In every case the clinical symptoms disappeared rapidly. Hyperfibrinaemia and hyperleucocytosis with granulocytosis regressed within one week, and high platelet counts within 2 to 3 weeks. the disappearance of immunological abnormalities paralleled that of clinical signs. Three-dimensional echocardiography showed dilatation of the left coronary artery in only one of the 30 children at 1 and 6 months, but coronary arteriography performed during the 6th month gave normal results. Intravenous immunoglobulin therapy seems to be effective in preventing the development of coronary aneurysms in patients with Kawasaki disease. The immunoregulatory function of immunoglobulins accounts for this effectiveness and for their value in immune diseases.

TWO TYPES OF RECOGNITION: Direct recognition occurs when the recipient's T cells recognize allogenic antigens presented by the donor antigen presenting cells. Indirect recognition occurs when donor antigens on recipient antigen presenting cells are recognized. DIRECT RECOGNITION: Direct recognition occurs during the first days or weeks after transplantation when naive recipient cells recognize donor dendritic cells that have migrated to secondary lymphoid organs. This explains why acute rejection occurs mainly during the first weeks after transplantation. INDIRECT RECOGNITION: This is certainly a less intense mechanism than direct recognition. It probably is involved in acute rejection but is known to play a major role in chronic rejection. CD4 cells that have been activated by indirect recognition play an essential role in activating B cells, leading to the formation of anti-HLA antibodies as well as in activating macrophages and monocytes, endothelial cells and smooth muscle cells. INDUCTION OF TOLERANCE: Three mechanisms of action for regulating the allo-immune response leading to graft tolerance have been put forward: consumption of interleukin-2, production of suppressive cytokins, direct or indirect suppressive contact. T CELL ACTIVATION: Knowledge of the intracellular signals induced by T cell receptor activation makes it possible to target key proteins that could be blocked leading to better immunosuppression than with calcineurin inhibition.