Long-term results of cyclosporine treatment in renal transplantation.
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Azathioprine↗
Biomedical subjects
C B Carpenter
Publications and source records attributed to C B Carpenter.
Clinical experience with cyclosporine and azathioprine at Brigham and Women's Hospital.
Cyclosporine (CsA) immunosuppressive therapy of renal allograft recipients at Brigham and Women's Hospital yielded a 20% increase in 12- and 24-month allograft survival over azathioprine (Aza) treated controls. A trend towards increased allograft survival with better HLA-A,B, or DR matching in recipients of cadaver allografts treated with CsA was appreciated, but it fell short of statistical significance. Nephrotoxicity is common in CsA-treated patients and is manifested by a largely reversible increase in the serum creatinine. It is possible to convert patients from CsA to Aza without adverse effects on allograft survival or allograft function.
Adult↗
Cyclosporine-induced transplantation unresponsiveness in rat cardiac allograft recipients: in vitro determination of helper and suppressor activity.
Lymphocytes from spleen, peripheral blood, thymus, and lymph node of naive rats, nonimmunosuppressed recipients of MHC-incompatible heart grafts, and cyclosporine-treated recipients of MHC-incompatible heart grafts were tested for their ability to augment or suppress proliferation of naive cells in an in vitro MLR co-culture assay. Rats treated with cyclosporine for only 7 days maintained their grafts indefinitely. Potent suppressor activity was found in the peripheral blood and spleen of adult naive rats. In untreated engrafted rats, increased suppressor activity was found 1 wk after transplantation and increased helper activity 2 wk after transplantation. In contrast, subnormal helper and suppressor activity was found in cyclosporine-treated rats 1 wk after transplantation. Subsequently, suppressor activity peaked at 2 to 3 wk and helper activity at 4 wk after transplantation. Beyond 5 wk, the cyclosporine-treated rat was indistinguishable from naive ungrafted rats. Two types of suppressor activity were identified that differed in buoyant density and cyclophosphamide sensitivity. Neither suppressor activity demonstrated antigen specificity. These data suggest that one role of cyclosporine in this rat model is to delay the initial helper mechanisms until generalized suppressor activity is operable. The increased antigen-nonspecific activity is only transient, presumably until the final antigen-specific mechanisms become operative.
Animals↗
Stability of renal allograft recipients after conversion from cyclosporine to azathioprine.
Forty-eight patients with stable renal function after allotransplantation have been converted from CsA/prednisone to azathioprine/prednisone to assess the short- and long-term effects upon renal function. Virtually all patients show an initial improvement in serum creatinine levels. Three patients developed chronic renal failure after 12 to 21 months, and three died of pneumonia 7, 12, and 19 months later. The mean serum creatinine level at latest follow-up (seven to 36 months) was 2.5 +/- 1.5 mg/dL for all 48 patients. Of interest, a control group of 21 patients not converted to azathioprine had serum creatinine levels of 2.5 +/- 0.8 mg/dL, over a follow-up period of five to 25 months. It is not immediately apparent that either group will have a superior overall outcome, although patients on azathioprine seem to have more of a risk for graft loss. More data are needed with various dosage schedules, and with randomized controls.
Acute Disease↗
Two genes required for diabetes in BB rats. Evidence from cyclical intercrosses and backcrosses.
The BB rat develops a syndrome of autoimmune diabetes similar to Type I diabetes of man. It also has a severe T cell lymphopenia. As part of an ongoing breeding program to transfer the diabetogenic genes of the BB rat onto inbred rat strain backgrounds, diabetic animals were used in a backcross (BC)- intercross (IC)-backcross breeding scheme with Brown Norway (BN), Lewis (L), and Wistar-Furth (WF) inbred rats. We have used monoclonal antibodies to analyze both lymphopenia and major histocompatibility (MHC) antigens (the RT1 locus in the rat) in relation to the development of diabetes. To examine T cell subsets we used a panel of monoclonal antibodies, in particular W3/25 and OX19 , which discriminate the abnormal phenotype better than W3/13. In our breeding program, at least two independent genes or gene complexes are required for the expression of diabetes. One gene determines the lymphopenia, is inherited by simple autosomal recessive genetics and is not linked to the MHC. The second gene is linked to the MHC. Both genes are necessary, but neither gene is sufficient by itself for the development of diabetes.
Animals↗
"Free-market" approach to organ donation.
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Cadaver↗
Immunosuppressive therapy for renal transplantation.
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Adrenal Cortex Hormones↗
Thy-1.1 in glomeruli of rat kidneys.
The antigenic composition of the rat kidney was studied by indirect immunofluorescence and immunoelectron microscopy using monoclonal antibodies against Thy-1.1 (OX7 and ER Ly 1), Thy-1.2 (30-H12), and W3/13 as well as rabbit antisera against rat brain or thymic blasts. The anti-Thy-1.1 reagents caused pronounced staining of the glomerular mesangium as well as a weak stain around some of the medullary collecting ducts and/or vessels. The rabbit antisera contained additional antibodies that bound to renal basement membranes and smooth muscle cells. This was confirmed by blocking and absorption experiments. The presence of Thy-1.1 in glomeruli was further demonstrated by in vivo perfusion studies with OX7 and rabbit anti-thymic blast serum. Immunoelectron microscopy of isolated glomeruli showed binding of OX7 antibodies to mesangial cells and the mesangial matrix. It is concluded that in rat kidneys the Thy-1.1 antigen is expressed on glomerular mesangial cells.
Animals↗
Experience with cyclosporine and steroids in clinical renal transplantation.
We have reviewed the results of patient survival and transplant function of the last 100 recipients of renal allografts treated with cyclosporine (CyA) plus low-dose steroids since November 1981; the follow-up varies between 3 months and 2 years. A group of 56 individuals transplanted between January 1980 and October 1982 and immunosuppressed with azathioprine (Aza) and steroids were used as comparison. There were five deaths among 100 patients treated with CyA and two among 56 treated with Aza. There were, however, marked differences in allograft function. Using actuarial curves, 2-year allograft survival from 24 living, related, one haplotype matched donors was 83%, as compared to an unsatisfactory 60% graft function among 24 nonrandomized, comparable, Aza-treated recipients. The 2-year actuarial survival of 76 allografts from cadaver donors was 76%; that of 36 grafts in patients treated with Aza, 48%. Interestingly, function of first cadaver allografts was 84% at 2 years, far better (p less than 0.002) than cadaver graft function (58%) in patients who had been previously transplanted; these latter results are comparable to Aza-treated cadaver recipients. Side effects and complications of this difficult drug, as well as its benefits, have been stressed in this article.
Actuarial Analysis↗
Conversion from cyclosporine to azathioprine in renal allograft recipients.
Fifty seven recipients of renal allografts initially treated with CsA and low-dose prednisone were switched to azathioprine and low-dose steroids. Ten had prolonged (greater than 28 days) allograft nonfunction after transplantation (group 1), 8 had ongoing, poorly controlled rejection (group 2), and 39 had stable functioning grafts (group 3). With a mean follow-up period of 5 +/- 3 months after conversion, 50 grafts remained functional including 6 of 10 in group 1, 6 of 8 in group 2, and 38 of 39 in group 3. Thirty-seven (65%) had improved function, 12 (21%) had stable function, and 8 (14%) experienced declining renal function. Three of these latter 8 patients required reinstitution of CsA therapy. There were 20 episodes of acute rejection in 18 patients; one graft lost function because of acute rejection unresponsive to therapy. Reasons for the 6 other graft losses were persistent primary nonfunction in 3 patients from group 1, untreated rejection in 2 patients who had multiple prior rejection episodes while on CsA, and chronic rejection in one patient. Although renal function has improved or stabilized in the majority (86%) of individuals changed to azathioprine therapy, there was substantial risk of acute rejection (32%) complicating this procedure. Patients most likely to benefit from conversion to azathioprine therapy are those with prolonged graft nonfunction after transplantation and those with serum creatinines greater than 2.0 mg/dl.
Adult↗
Cyclosporine: a new immunosuppressive agent for organ transplantation.
Cyclosporine, a cyclic endecapeptide of fungal origin, has recently been released for use in clinical transplantation. Trials in kidney, heart, liver and bone marrow recipients were encouraging: 1-year graft survival rates were 70% to 80% for kidney and heart recipients, and 60% to 65% for liver allograft recipients. Cyclosporine is also effective in treating bone marrow recipients with acute graft-versus-host disease. The drug selectively inhibits T-helper cell production of growth factors essential for B cell and cytotoxic T-cell differentiation and proliferation, while allowing expansion of suppressor T-cell populations. Drug absorption varies greatly, necessitating monitoring of drug level and individualization of therapy. Nephrotoxicity is the most frequent side effect of cyclosporine. An increased incidence of B-cell lymphomas seen when cyclosporine was used in conjunction with cytotoxic agents or anti-lymphocyte globulin has very rarely been observed when concomitant immunosuppression has been limited to low-dose corticosteroids. Lower initial doses of cyclosporine, followed by more rapid tapering may reduce the incidence of nephrotoxicity without compromising improved graft outcome.
Animals↗
Immune reactivity and immunosuppressive intervention in experimental nephritis. II. Effect of TLI on the course of two models of nephritis in the inbred rat.
Fractionated high-dose (3400 rad) total lymphoid irradiation (TLI) induces a unique and prolonged state of immunologic unresponsiveness. The therapeutic efficacy of TLI in immune glomerular disease was explored in two animal models: the accelerated autologous form of nephrotoxic serum nephritis (AA-NTSN) and autologous immune complex nephritis (AICN). LEW rats with established AA-NTSN, subjected to TLI, manifest decreased levels of circulating antibody to the heterologous (sheep) immunoglobulin G (0.4 +/- 0.2 vs 1.2 +/- 0.3 mg/ml, mean +/- SE respectively, p less than 0.01) early post TLI in association with a reduction in histopathology and albuminuria (6.7 +/- 2.2 vs control 19.6 +/- 5.4 mg/24 hr, mean +/- SE, p less than 0.02). Administration of TLI to rats with established AICN effected significant (p less than 0.001) reduction in albuminuria (162 +/- 30 vs 315 +/- 27), serum creatinine (p less than 0.005), and the incidence of lipemia (p less than 0.01) vs controls. Adoptive transfer studies provided no evidence that the sustained beneficial effect of TLI in AICN was suppressor cell mediated. Thus, the observed therapeutic efficacy of TLI in the treatment of experimental nephritis, shown to be related to a reduction in the level of circulating antibody in AA-NTSN, provides a new model system for study of immunity and immunosuppression in primary glomerular disease.
Albuminuria↗
T cell synergy in the primary MLR: proliferative kinetics, effector cell generation, and IL 2 production.
A primary rat MLR was initiated, and on each of 8 consecutive days during the evolving culture, an aliquot of cells was separated into its constitutive helper/inducer (W3/25+) and suppressor/cytotoxic (OX8+) T cell subsets by a monoclonal antibody, Degalan-bead immunoadsorbent column technique. This allowed a detailed kinetic analysis of T cell proliferation, the generation of effector cells, and the production of IL 2 by each subset relative to net whole culture supernatant IL 2 activity. The primary MLR demonstrates an early period of helper/inducer cell proliferation, IL 2 production and accumulation, followed by a period of suppressor/cytotoxic cell (OX8+) proliferation and IL 2 consumption during which there are distinct waves of allospecific suppressor, followed by cytotoxic activity. If fresh T cells of the helper/inducer or suppressor/cytotoxic phenotype were preseparated and then cultured alone with irradiated allogeneic stimulator cells, proliferation was noted in both subsets despite no demonstrable IL 2 activity in cultures of the suppressor/cytotoxic cells. Finally, a suppressed primary MLR exhibited proliferative inhibition of both T cell subsets.
Animals↗
Dual parameter flow cytometric analysis of DNA content, activation antigen expression, and T cell subset proliferation in the human mixed lymphocyte reaction.
This study provides direct correlation via dual parameter flow cytometry (simultaneous assessment of immunofluorescence and DNA content) between mixed lymphocyte reaction (MLR) responder cell entry into the S/G2/M phases of the cell cycle with the kinetics of expression of two activation-associated cell surface proteins, Tac (IL 2 receptor) and 4F2 (unknown metabolic function). A small population of activated cells was identifiable by expression of both Tac and 4F2 antigens before peak DNA synthesis in the MLR. This population of activation antigen-positive cells expanded linearly in size from days 3 to 7 of culture. Treatment of immature MLR cultures with anti-4F2 Mab and complement (C) before DNA synthesis (treatment on day 3, peak DNA synthesis on days 5 to 6) resulted in blunted proliferation and activation antigen expression when the same culture was analyzed after maturation on day 6, indicating that the activated population had been previously detected and removed by anti-4F2 Mab + C. The 4F2 antigen was expressed on a greater percentage of cells in the MLR at all times (days 3 to 9) than was Tac, was present on virtually all S/G2/M phase responder cells, and a large fraction of cells remained intensely 4F2+ subsequent to peak DNA synthesis. In contrast, after initially preceding responder cell entry into the S phase of the cell cycle, the kinetics of Tac antigen expression closely paralleled the kinetics of responder cell proliferation. A subpopulation of cycling responder cells was noted in all MLR cultures studied that expressed Tac antigen weakly or not at all. Cells within both T4 and T8 cell subsets proliferate with similar kinetics in response to alloantigen. The possibility that activation antigens can be utilized to study effector cell generation in the MLR and that this flow cytometric technique may be utilized to analyze the response to various alloantigens is discussed.
Antigens, Surface↗
Sharing of HLA haplotype by parents of patients with systemic lupus erythematosus.
Forty-four families were studied for the relationships between HLA and systemic lupus erythematosus (SLE). Nine families had more than 1 member with SLE; haplotype sharing between SLE patients within a family was no greater than expected by chance. Fourteen of 236 relatives had antinuclear antibodies (ANA); the frequency of haplotype sharing between SLE patients and ANA-positive relatives was no greater than expected by chance. One HLA-A,B haplotype was shared by 7 of 35 parent pairs, a frequency (20%) significantly greater (P = 0.004) than in 2 groups of normal controls (3.1% and 5%). These data provide evidence for HLA-linked genes operating recessively in the expression of SLE.
Alleles↗
Antithymocyte globulin, pretransplant blood transfusion, and tissue typing in cadaver kidney transplantation.
Three hundred forty-seven recipients of primary cadaver kidney transplants were analyzed in relation to ATG therapy, pretransplant transfusion, HLA-A, -B and -DR antigen matches, and level of PRA to the panel. Prophylactic ATG treatment increased transplant survival significantly when compared with the non-ATG group. The beneficial effect of pretransplant blood transfusions was not apparent when the recipients received prophylactic ATG treatment. No correlation was noted between HLA-A and -B antigen matches and transplant survival. There was no significant difference in the transplant survival between patients with zero DR antigen match kidneys and those with one DR antigen-match kidney. The number of transplants with two DR antigen-match kidneys was too small to be conclusive. The recipients in whom PRA did not develop despite pretransplant blood transfusions seemed to have better transplant survival than those in whom PRA did develop in response to blood transfusions.
Antilymphocyte Serum↗
Transplantation: immunogenetic and clinical aspects--part II.
The ultimate goal is not merely to find a better way of treating acute rejection; efforts are now concentrated on prophylactic immunosuppression with low-dose regimens of azathioprine and steroids. In the wings is cyclosporine, a fungal polypeptide that shows great promise in clinical trials. And on the horizon there is hope that monoclonal antibodies may hold the key to prevention.
Adult↗
Prostaglandin as an effective antirejection therapy in rat renal allograft recipients.
Because adenylate cyclase activators such as prostaglandin E1 elevate lymphocytic cyclic AMP and inhibit T cell proliferation and the effector function of cytotoxic T cells in vitro, we tested the efficacy of 15(S)-15-methyl prostaglandin E1, a prostaglandin derivative with a prolonged biologic half-life. Treatment with this agent resulted in a near complete protection of renal grafts from immunologic damage, despite withholding therapy until day 4 following transplantation.
Alprostadil↗