Release of interleukins during tolerance and rejection of human renal allografts.
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Biomedical subjects
Publications and source records attributed to B Charpentier.
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A prospective study was conducted on 57 high-risk patients having received cadaver renal transplants between January 1983 and May 1984, and submitted to the triple combination: cyclosporine, azathioprine, and steroids. 23 patients of Group I including 12 pre-sensitized and poorly matched recipients were treated from the Day 1 post-transplant. 34 patients of Group II received the triple combination following a steroid-ALG resistant rejection. Actuarial graft survival in the whole group was 74%, 64%, and 64% at 1, 2, and 3 years respectively. Patient survival was 100% in the Group I, vs 85% at 1 year, and 82% at 2 years in the group II (p less than 0.02). The incidence of infectious complications and infectious deaths was significantly higher in patients of Group II. Our results suggest the effectiveness of a triple low-doses combination in high-risk renal transplantation, but the delayed use of this combination following a treatment with high-doses of steroids and ALG fails to reverse the rejection, with an obvious overimmunosuppression risk.
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We report seven cases out of eight reversible raises (350% of mean increase) of cyclosporine (CsA) plasma levels in patients receiving the new calcium channel blocker nicardipine (Loxen-Sandoz) and CsA after renal transplantation. Nicardipine was introduced 3 to 36 weeks post transplantation in 7 cases of hypertension and 1 case of angina pectoris. CsA plasma levels raised considerably 1 to 30 days after nicardipine introduction and returned to pretreatment levels 1 to 7 days after withdrawal. Serum creatinine increased in 1/8 patients. These data suggest that nicardipine interferes with CsA metabolism and this interaction is reversible after nicardipine discontinuation. These findings point out the fact that at least some calcium channel blockers need to be cautiously used in patients receiving CsA.
Following development of dilatation on ultrasonography and/or intravenous pyelography in the course of follow-up after renal transplantation, a dilatation due to obstruction must be distinguished from dilatation without obstruction. DTPA scintigraphy is frequently used for the diagnosis of hydronephrosis caused by an anomaly of the pyeloureteric junction. In renal transplantation, this examination is used less frequently. The authors report a prospective study of Lasilix scintigraphy in the diagnosis of obstruction in 30 renal transplant. The results presenting with stasis of their transplant. The results were classified into 4 groups according to O'Reilly's classification and were compared with the course of the stasis. Lasilix scintigraphy demonstrated a specificity of 93% and a sensitivity of 63%. The role of stasis in the deterioration of the renal function of a transplant is difficult to evaluate. In cases of stasis with altered renal function, the authors propose the addition of study of the renal parenchyma by renal biopsy, which excludes rejection and Cyclosporin nephrotoxicity. When the renal biopsy is normal, the kidney should be drained by percutaneous nephrostomy which evaluates the capacity of recovery of renal function and determines the indication for antegrade dilatation or surgical repair.
A prospective study on digital intravenous angiography (DIVA) in 164 renal transplant recipients performed from 1 to 2 months post-transplant was conducted to assess its usefulness in the screening of post-transplant renal artery stenosis (RAS). DIVA was uninterpretable in 32 patients (19%) on technical grounds (blood vessel or metallic clip superimposed). The global prevalence of RAS was 10.7% in 132 patients whose DIVA was informative. No correlation was found between the prevalence of RAS and renal function. The prevalence of RAS was significantly higher (p less than 0.01) in the hypertensive (26%) than in the normotensive group (6.6%), but RAS may occur in normotensive or even asymptomatic patients. Our data confirm the usefulness of routine post-transplant renal artery screening but arterial way will be preferred.
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We developed an in vitro system for the generation of human cytomegalovirus (CMV)-specific cytotoxic T cells (CTL) that avoids the necessity of constituting a panel of HLA-typed fibroblasts. Autologous donor leucocytes were coated with CMV antigens and were used as both stimulator and target cells. With the use of this system, CMV-specific effector cells were efficiently generated from seropositive but not seronegative donors. These CMV-specific effectors were HLA-restricted and had characteristics of T cells. Maximum lymphoproliferation preceded the appearance of maximum CTL activity by 3 to 4 days, and a close correlation was seen between both activities. Mouse anti-CMV monoclonal antibodies were used in blocking experiments in an attempt to define target antigens recognized by CMV-specific cytotoxic lymphocytes. Monoclonal antibodies directed against an early CMV membrane antigen, against neutralization epitopes, or against nuclear inclusion body protein all specifically inhibited CMV-sensitized effector cell activity but did not affect influenza virus-specific lysis. Monoclonal antibodies directed against a normal cell determinant or against poliovirus did not affect CMV-specific CTL activity. CMV-immune cytotoxic T cells could be consistently and specifically inhibited in their lytic activity by pretreating antigen-coated target cells with monoclonal antibodies directed against CMV-related proteins.
Clometacin is an antalgic drug with a chemical structure very similar to that of indomethacin; it is widely used in France. We report evidence for a cell-mediated immune mechanism in the pathogenesis of clometacin-induced acute interstitial nephritis. In the interstitial infiltrate of a female patient presenting with this condition, T cells constituted 75% of the total lymphocyte population. Cytotoxic/suppressor T cells predominated over helper/inducer T cells with a ratio of two to one. IgA-secreting plasmocytes were also present (about 23% of the inflammatory infiltrate). Peripheral blood lymphocyte studies showed that pre-incubation of the patient's cells with clometacin resulted in an increased sensitivity to interleukin 2 and a positive syngeneic mixed lymphocyte culture. This study seems to be relevant to the pathogenesis of acute interstitial nephritis induced by nonsteroidal anti-inflammatory drugs.
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Four hundred and thirty renal transplantations have been performed over a 5-year period during which there was a switch of surgical technique towards uretero-vesical anastomosis. In this paper, the urological complications observed are studied according to the site of transplantation, the position of the kidney, the type of anastomosis and the length of the ureter. Kidneys that were transplanted in iliac position gave rise to more complications than those transplanted in pelvic position, and reversing the kidney increased the number of urological complications. The complication rate was 6.7% with the uretero-vesical anastomosis and 12% with the uretero-ureteral anastomosis. The best results were obtained when the kidney was transplanted into the iliac fossa in pelvic position with its upper pole upward and its ureter anastomosed with the bladder: in 274 transplantations performed with this technique the complication rate was 4.7%. This study of different types of transplantation shows that the main factor is the ureteral length utilized: the longer that segment of the ureter, the more numerous the urological complications.
Degradation of Boc-CCK27-33 [Boc-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-PheNH2) a fully potent analog of CCK8 was studied on synaptic plasma membranes from pig brain cortex. Characterization of the metabolites was performed by HPLC. This allowed to show the hydrolysis of the Asp-Phe bond by the neutral endopeptidase "enkephalinase", and the cleavages at the Met-Gly and Trp-Met bonds by PCMB sensitive enzymes. Similar results were observed using Boc(diNle28,31)-CCK27-33 as substrate. To investigate the biological relevance of these enzymes in the CCK8 metabolism, the degradation studies were performed on rat brain slices, with [3H]Boc(diNle28,31)CCK27-33 as substrate. Using these more physiological preparations i.e. striatal or cortex slices, the tritiated probe was cleaved at the Nle-Gly and Gly-Trp bonds. These degradation pathways were almost completely inhibited by PCMB, but in the striatum this inhibition process induced the appearance of a small peak corresponding to the action of enkephalinase. Taken together these results seem to indicate that thiol proteases play a crucial role in the CCK8 metabolism but that enkephalinase is virtually not involved.
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The rejection of an allograft is a complex phenomenon involving various subsets of immune cells. If the role of humoral immunity and cytotoxic T cells is well demonstrated, helper T cells have also a major effect in some models of allograft destruction. Moreover, Natural Killer cells, Killer cells, monocytes/macrophages, B lymphocytes are also implicated in various stages of graft rejection. The analysis of the clonal repertoire of T lymphocytes, the discovery of the structure and function of the T-cell receptor and finally the genetic control by encoded genes of the immune response may lead to a better comprehensive and therapeutic approach of graft rejection.
The authors report a case of testicular malakoplakia in a renal transplant patient. They emphasise the predisposing role of immunosuppression which was particularly intense in this patient and they stress the risk of dissemination of the disease to the graft.