Biomedical subjects
Publications and source records attributed to J Kaden.
Application of OKT-3 as rescue therapy in steroid-resistant rejection was effective in 7 out of 9 patients early after cadaveric kidney transplantation. Under attention of instructions for use of OKT-3 the adverse first-dose reactions are rare. The problem of OKT-3 therapy is early use and its reuse.
In a retrospective study of 326 patients which have been received a renal allograft between 1985 and 1988 at the Berlin Kidney Transplant Centre, all recipients were divided into 3 groups according to their antibody status against cytomegalovirus (IgM+/IgG+; IgM-/IgG+; IgM-/IgG-). Frequency and severity of CMV infections in the early period after kidney transplantation have been compared. Primary infections could be observed in 51/112 (45.5%) patients (group 3), secondary infections in 60/190 (31.6%) patients (group 2). In 7.4% of all recipients (24/326) CMV-specific IgM antibodies could be found at the time of transplantation (group 1). In primary infections the patients have had a significantly higher frequency of moderate or severe CMV diseases as in secondary infections (24.4 vs. 8.3%). In group 3 this frequency was 16.7%. In conclusion, it is not necessary to select renal allograft recipients according their positive CMV-IgM-antibody status, but a close-meshed posttransplant control is indicated.
The treatment of transplants by a combination of 8-methoxypsoralen and longwave ultraviolet radiation (PUVA) leads to prolongation of the transplants in allogeneic receivers without immunosuppression. The rejection of skin grafts in the mice could be delayed significantly. The rejection of kidney and heart allografts could be prevented completely. A significant diminution of the acute rejection crises and a raising of the one-year survival rate showed a first clinical study by means of PUVA treatment in human kidney grafts.
Kidneys were removed ten minutes after treating the donor with 1 mg of 8-methoxypsoralen per 1 kg b.w., during hypothermic preservation UVA-irradiated (intensity: 1.34 mJ/s) for 4 h and thereafter transplanted into ASDI dogs (n = 10). Fine needle aspiration biopsies were performed to analyze the inflammatory response. In comparison with untreated ASDI dogs (n = 9) PUVA pretreated renal grafts showed three important differences: 1. At the peak of the rejection process in the control group (day 8) the cellular infiltrate in the PUVA-pretreated kidneys was significantly diminished. 2. This reduction was caused by a significantly lower influx of monocytes/macrophages. 3. The peak of the cellular response in the PUVA group was delayed. These findings support the concept of reduced graft immunogenicity by pretransplant PUVA treatment.
In 56 kidney transplant recipients 93 specimens from transplant aspiration biopsy and peripheral blood were examined on the presence of cytomegalovirus (CMV) using the monoclonal antibody (mab) H 11. The used mab H 11 did react safe and exclusive in the acute infection period with the virus antigen. This antigen detection makes possible the laboratory diagnosis of a CMV infection 11 days (median value) prior to detection of specific IgM antibodies. In comparison with the cytological evaluation of fine needle aspiration biopsy the rejection process could be differentiated from infection.
In 10 patients after kidney transplantation the T cell subpopulations (CD4, CD8) and the number of activated lymphocytes (IL-2R and transferrin receptor+, 4F2+, HLA-DR+, CD3+) in the peripheral blood were determined. In 9 out of 9 cases with rejection a clear immune activation could observed. In patients with CMV-associated rejection crisis the CD4/CD8 ratio was significantly higher compared with patients with rejection crisis but without CMV infection. In all patients with CMV infection (n = 5) an increase of activated lymphocytes was observed. In a clinical-immunological monitoring the dynamics of the CD4/CD8 ratio, the expression of activation marker (especially CD3+, HLA-DR+ and 4F2+) and the absolute number of lymphocyte subpopulations should included.
Dose-response studies of cyclosporin (CsA) established that a dose of 2 mg kg body weight on day 0 was of therapeutic suboptimal value in rat kidney allotransplantation. When PUVA-treated heart and kidney allografts were transplanted into temporary CsA immunosuppressed recipients the graft survival rates were further improved as compared with PUVA alone. Forty vs. 18% (heart) and 70 vs. 40% (kidney) of the PUVA + CsA vs. PUVA treated allografts survived permanently. Therefore a synergistic effect of PUVA pretreatment and low-dose CsA therapy on rat heart and renal allograft survival was demonstrated.
The excretion capacity of 24 kidney allografts which had been dialyzed because of non-function was examined. It has been shown that only 4 out of 24 allografts (16.7%) were truly without function. All other transplants did show a slight or more improvement of the excretion capacity prior to irreversible loss of graft function. As a cause the non-identified graft rejection is discussed.
The aim of the present study was to evaluate the influence of a pretreatment of the heart and kidney donor with the photosensitizer 8-methoxypsoralen plus ex vivo longwave ultraviolet irradiation of the graft (PUVA) on survival time and immunogenicity of rat heart and kidney allografts. PUVA pretreatment significantly prolonged the survival of these transplants in allogenic recipients. Furthermore, a synergistic effect with conventional immunosuppression (azathioprine, cyclosporine) was demonstrated. Immunohistological studies using monoclonal antibodies showed a significant reduction of MHC class II antigen expression in heart cryostat sections after PUVA treatment. In clinical kidney transplantation the number of rejection episodes was significantly lower in the first 3 months in the PUVA-treated patient group.
The purpose of these experiments was to evaluate the influence of pretreatment of the heart donor with the photosensitizer 8-methoxypsoralen plus ex vivo longwave ultraviolet irradiation of the graft (PUVA) on survival time and immunogenicity of rat heart allografts in a donor-recipient combination that was different at the major histocompatibility complex (MHC). PUVA treatment of the donor hearts significantly prolonged their survival in allogeneic recipients. The efficacy of this therapy was dependent on the time of ultraviolet irradiation. Immunohistological studies using monoclonal antibodies to rat MHC class I and II antigens showed a significant reduction of class II antigen expression in heart cryostat sections after PUVA treatment. No differences were seen in the tissue distribution of class I antigen. This reduction of donor MHC class II antigens may influence the antigen presentation as well as the activation of T helper cells. In conclusion, PUVA treatment is effective to reduce the immunogenicity and to improve the graft survival time of rat heart allografts. These experimental findings are new and suggest a possible clinical application of photochemical pretreatment.
Systemic photochemical pretreatment of a rat kidney donor with the photosensitizer 8-methoxypsoralen (8-MOP; 0.06 mg/kg intravenously, 10 min before graft removal) plus ex vivo longwave ultraviolet (UVA) irradiation of the kidney graft during simple hypothermic storage significantly prolonged survival time in allogeneic recipients. In contrast to these results, the present use of UVA irradiation during hypothermic pulsatile kidney perfusion using Euro-Collins solution containing 8-MOP (0.06 mg/ml) did not prolong graft survival compared with untreated controls. Systemic application of 8-MOP to the kidney donor may be necessary for effective action of the combined photochemical treatment as a method of immunoalteration. The extended UVA irradiation time and the local use of 8-MOP in the preservation fluid had no effect on graft survival possibly because of inadequate tissue distribution of 8-MOP during both hypothermia and perfusion.
The pretreatment of both kidney and heart donor with the photosensitizer 8-methoxy-psoralen followed by in vitro longwave ultraviolet graft irradiation (PUVA therapy) significantly prolonged graft survival times in rats even across a strong major histocompatibility complex (MHC) barrier. Immunohistological studies using monoclonal antibodies (Mab) to rat MHC class I and II antigens showed a significant reduction of class II antigen expression after PUVA therapy in both Sprague-Dawley rat kidneys and hearts. Using MHC class I Mab there were no differences in distribution pattern in untreated as well as in PUVA treated organs. Thus, our results represent the first in vivo evidence that photochemotherapy-induced graft survival time prolongation is closely connected with its ability to reduce MHC class II antigen expression.
Twenty retransplant patients were serially screened for donor-reactive antibodies (DRA). DRA appeared exclusively in patients whose grafts permanently failed and these DRA shared some common features, namely early appearance (days 4-8 post-transplant), high titers (1:10 up to more than 1:400), and broad anti-HLA specificity. This preliminary data would suggest that regrafted patients with primary graft failure represent a distinct subgroup of particularly immune responsive individuals.
Photochemical pretreatment of the kidney donor (Sprague-Dawley rats/SD) with 8-methoxypsoralen (8-MOP) and ex vivo longwave ultraviolet (UVA) irradiation of the kidney graft (PUVA therapy) significantly prolonged survival in allogeneic recipients (BD IX rats). After more than 100 days 7 long-term surviving PUVA-pretreated SD kidneys were retransplanted into BD IX rats. Seven out of 7 secondary recipients survived for more than 100 days. Twenty BD IX recipients of normal SD kidneys were treated at the time of transplantation with serum (1 ml i.v.) and/or spleen lymphocytes (1 X 10(7) i.v.) obtained from the PUVA-treated long-term survivors. A prolonged graft survival was achieved in 7 out of 20 rats, among them 4 out of 8 recipients of the serum-treated group. In conclusion, the long-term survival of PUVA-treated rat renal allografts is associated with a strong reduction of graft immunogenicity and the development of graft protecting humoral as well as cellular effectors.
Extended experimental experience with the efficacy of pretreating the kidney donor and the allograft by means of photochemotherapy (photosensitizer + UVA irradiation = PUVA) was adopted in clinical kidney transplantation. In a preliminary unrandomized study similar patient populations were treated by generally uniform methods. Thirty-three PUVA-pretreated kidneys (group A) were compared with the experience regarding 26 non-pretreated kidney allografts (group B). The number of rejection episodes was significantly lower in the first 3 months in group A (p less than 0.05 vs group B) and fewer grafts failed because of irreversible rejection (2 vs 5). Furthermore, in group A the rate of infectious complications was lower (18% vs 34%). The cumulative allograft survival at 3 months was improved from 65% in group B to 81% in group A and at 12 months from 65% 76%, respectively. These differences were not significant. Therefore, our preliminary clinical experience with a photochemical donor pretreatment is encouraging and further use in a randomized study seems to be necessary.
High titre plasmas gained from blood donors are the initial material used for producing human immunoglobulin containing cytomegalovirus antibodies (CMV-HIG). For this purpose the sera gained from 467 permanent donors at the District Institute for Blood and Transfusion Service in Berlin were investigated on their CMV antibody content of IgG class by means of an indirect immunofluorescence test (IFT). The infection rate of blood donors amounted to 62% (291/467). CMV-IgG titre greater than or equal to 1:40 was determined in 88 sera (18.8%) and greater than or equal to 1:160 in 14 sera (3%). Two CMV-HIG laboratory samples (charges 3113 and 3117) were produced from these plasmas. Particularly immunoglobulin fraction of charge 3117 (No. 3117 N II) revealed excellent antibody titres (IFT 1:640 [CMV-IgG] or 1:40 [CMV-IgM] respectively, neutralisation test 1:32). Checks made with the donors' CMV-IgG titres after repeated application of plasmapheresis resulted in maximal titres changes of two dilution stages in a period of 15 months. Thus, in producing CMV-HIG a sure, tested pool of donors can be resorted to.
We used the strength of suppression of the interleukin-1-induced peak CRP response (CRPmax) post-transplant as a measure for the individual steroid susceptibility in vivo. This suppressive effect proved to be fully reversible after abrogation of steroid therapy following graft removal. The standardized suppressive therapy immediately post-transplant led to extremely different results in individual patients ranging from no suppression (26.1% of the patients) to a strong or practically absolute suppression of CRP synthesis in 20.7% of the patients studied. This behaviour is also reflected in anti-rejection bolus therapy whereby the percentage of prednisolone resistant patients strongly correlated with increasing (unsuppressed) CRPmax values. From our data we conclude that the disparate anti-inflammatory susceptibility for corticosteroids seems to be an individual feature of patients under high-dose steroid treatment.
Dose-response studies of cyclosporin (CsA) established that doses of 2 mg/kg body weight on 4 consecutive days (0-3) or higher gave complete suppression of rejection and permanent survival of all rat kidney allografts, while a dose of 2 mg/kg body weight on day 0 was much less effective in preventing deleterious rejection (30% permanent survival). Photochemical pretreatment of the kidney donor with 8-methoxypsoralen (8-MOP) and direct long-wave ultraviolet irradiation (UVA) of the kidney (PUVA) therapy) significantly prolonged the subsequent graft survival in allogeneic recipients. Forty per cent of the animals survived more than 100 days. However, when PUVA-treated kidney allografts were transplanted into temporary CsA immunosuppressed recipients (2 mg/kg on day 0) the graft survival rate was further improved. Seventy per cent of the PUVA + CsA-treated recipients survived permanently. Therefore, a synergistic effect of PUVA pretreatment and low-dose CsA therapy on rat renal allograft survival was demonstrated. The results suggested a possible clinical application of this treatment regimen in order to avoid high nephrotoxic CsA doses.