[Postoperative immunosuppressive therapy for our patients with heart transplantation done in United States].
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Anti-Inflammatory Agents↗
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T10B9 (MEDI-500) mediated immunosuppression: studies on the mechanism of action.
The murine IgM anti-human CD3/TCR mAb T10B9 is an effective agent for the reversal of acute cellular renal allograft rejection which offers several advantages over conventional OKT3 therapy. These include reduced morbidity and a more rapid decrease in serum creatinine levels. In the studies presented here comparing T10B9 and OKT3, soluble T10B9 is shown to be a nonactivating anti-T cell mAb. Evidence for its lack of activating potential includes in vitro failure to stimulate PBMC proliferation either alone or in the presence of nonmitogenic doses of phorbol ester, failure to induce the expression of early and late activation antigens and failure to induce IFN-gamma, TNF-alpha, IL-6 or IL-2 release. Analysis of acute renal allograft rejection patient plasma cytokine levels 2 h after the first dose support the hypothesis that T10B9 has reduced immunoactivation activity in vivo. Both TNF alpha and IFN gamma patient plasma levels are significantly reduced in T10B9 as compared to OKT3 therapy. However, T10B9 is capable of cellular signaling as demonstrated by its ability to induce apoptosis and IL-2 release in the human T cell line Sup-T13. Thus T10B9 retains the potent immunosuppressive activity of OKT3 with reduced immunoactivation.
Antibodies, Monoclonal↗
OKT3 induction therapy: influence of duration on rejections and infections.
Anti-lymphocytes induction therapy in renal transplants remains controversial relative to efficacy and cost benefit. It has been suggested that shortening the duration of induction therapy from 14 to 7 d would provide adequate efficacy at less cost. Our objective was to compare the efficacy and complications of short (7 d or less, group A) versus standard (14 d or more, group B) duration of OKT3 induction therapy in renal allograft recipients. We performed a retrospective review of all renal allografts performed between July 1989 and September 1994. Two groups were identified based on the duration of OKT3 induction therapy. There were no significant differences between group A or B in the distribution of age, sex, race, degree of HLA matching, and etiology or renal failure. Patients in group B experienced fewer rejections at 3 and 12 months (p = 0.0236 and p = 0.0065, respectively) as well as fewer viral infections during the first year of follow-up (p = 0.0435). No difference on the mean number of bacterial or fungal infections existed between the two groups. There were no statistically significant differences in patient or graft survival, although patients in group B had a tendency towards increased 1-yr graft survival.
Adolescent↗
Impact of first acute rejection episode and severity of rejection on cadaveric renal allograft survival.
A total of 504 renal transplants were performed between 1984 and 1993; 408 (81%) were cadaver grafts. This study evaluated the impact of a first acute rejection episode and the severity of the rejection on cadaveric allograft survival. Acute allograft rejection was based on clinical evaluation and confirmed by renal biopsy. Ten patients were excluded from this study due to early patient or graft loss. Patients were divided into Group I (n = 179), who never experienced acute rejection, and Group II (n = 219), who had an acute rejection episode. Group II patients were divided into IIA (n = 140), who had a mild first acute rejection episode treated with methylprednisolone, and IIB (n = 79), who had moderate or severe acute rejection treated with OKT3. The overall 1-, 2-, 3-, and 5-yr actuarial cadaveric renal allograft survival for Group I was 80%, 76%, 74%, and 68%. The corresponding graft survival for Groups IIA and IIB were 75%, 63%, 58%, and 50%; and 79% 71%, 65%, and 53% [p = 0.03 (I vs IIA), p = NS (I vs. IIB and IIA vs IIB)]. A similar pattern of survival was seen in primary kidney allograft recipients. In conclusion, long-term graft survival was superior in patients who never experienced acute rejection compared to those with rejection. Improvements in long-term graft survival can be accomplished in patients with severe rejection with OKT3 treatment resulting in comparable survival to those with mild rejection.
Actuarial Analysis↗
CD3+ CD8+ CTL activity within the human female reproductive tract: influence of stage of the menstrual cycle and menopause.
The human female reproductive tract (RT) has been analyzed by others with respect to NK cell cytolytic activity, but not CD3+ T cell (CTL) cytolytic activity. Here, we describe the cytolytic capacity of mucosal CD3+ T cells both longitudinally within the RT (Fallopian tube, uterine endometrium, endocervix, ectocervix, and vaginal mucosa) and temporally throughout the menstrual cycle, using a redirected lysis assay system. Cytolysis by CD3+ CD8+ T cells is found throughout the RT and appears to be hormonally regulated, since in the uterine endometrium, the capacity for CD3+ T cell cytolytic activity is present during the proliferative phase of the menstrual cycle and absent during the subsequent secretory (postovulatory) phase. In contrast, in postmenopausal women the entire RT, including the uterus, retains the capacity for strong CD3+ T cell cytolytic activity. These findings suggest that the high levels of estradiol and progesterone present during days 14 to 28 of the menstrual cycle down-regulate CTL activity in the uterus. As a consequence, the absence of this activity may allow implantation of a semiallogeneic embryo that would otherwise be rejected. Further, these studies indicate that CTL activity is regulated differentially in different regions of the RT, persisting in the cervix and vagina throughout the menstrual cycle.
Adult↗
OKT3 therapy increases cyclosporine blood levels.
Numerous drugs have been reported to alter cyclosporine (CSA) blood levels, most notably, those drugs that interfere with cytochrome P450 metabolism. Our clinical experience suggested that OKT3 therapy may alter CSA blood levels as well. The purpose of this study was to assess the effect of OKT3 therapy on CSA trough blood levels. We reviewed medical records of all CSA-treated renal transplant recipients during a 3-yr period to identify patients who received antilymphocyte induction therapy. Patients receiving drugs known to interact with CSA were excluded from analysis. The study population (n = 33) was divided into two groups: the OKT3 group consisting of 17 patients who received OKT3 therapy for 7 d post-transplant (OKT3 group) and the control consisting of 16 patients who received ALG induction therapy for 7 d post-transplant (ALG group). Oral CSA (14 mg/kg) was administered preoperatively. Postoperatively, oral CSA (4 mg/kg) was administered twice daily, in addition to corticosteroids and azathioprine. We evaluated CSA through levels on days 1, 3, 5, and 7 of antilymphocyte therapy and 3 d following completion of antilymphocyte therapy. On days 1 and 3, CSA trough levels did not differ between the two groups. However, median CSA trough levels (HPLC) were significantly higher among OKT3-treated patients on day 5 of therapy (265 ng/ml), as compared to ALG-treated patients (136 ng/ml; p < 0.0001; Mann-Whitney U-test). On days 7 and 10, CSA trough levels did not differ between the two groups. CSA does, however, had been adjusted based on levels obtained on day 5. We conclude that OKT3 therapy causes a significant rise in CSA trough levels. Recognition of this potential drug interaction is essential in titrating CSA doses in the early post-transplant period to minimize risks of CSA toxicity or early rejection following induction therapy.
Adult↗
New insights into therapy with monoclonal antibodies in allograft transplantation.
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Antibodies, Monoclonal↗
Pentoxifylline promotes replication of human cytomegalovirus in vivo and in vitro.
OKT3 monoclonal antibody (MoAb) therapy is well established in the prevention and therapy of acute rejection in transplant patients. Unfortunately, this therapy is associated with several short-term (cytokine release syndrome) and long-term (infections, EBV-related lymphoma) side effects. Recently, we were able to demonstrate an association between the TNF alpha release following the first OKT3 MoAb infusions and the appearance of human cytomegalovirus (HCMV) reactivation several days later. In order to prevent this TNF alpha associated HCMV reactivation patients were additionally treated with pentoxifylline (PTX), a methylxanthine derivative that has been shown to suppress TNF alpha induction. Although the TNF alpha peak plasma level following OKT3 MoAb treatment was markedly reduced, the incidence of HCMV reactivation and HCMV disease was not influenced. In transient transfection experiments using HCMV immediate early enhancer/promoter CAT reporter gene constructs PTX enhanced the promoter activity independently from TNF alpha in premonocytic cells. Furthermore, PTX acted synergistically with TNF alpha. In virus-infected human embryonal lung fibroblasts HCMV replication was triggered in the presence of both PTX and TNF alpha, while either substance alone had only marginal effects. The stimulatory effect of PTX on the immediate early (IE) enhancer/promoter was mediated via CREB/ ATF, a eukaryotic transcription factor that binds to the 19 bp sequence motif in the enhancer region, while TNF alpha stimulation was mediated by activation of the transcription factor NF-kappaB and its binding to the 18 bp sequence motif in the enhancer. These data suggest a potential side effect of cAMP-elevating drugs such as PTX.
Acute Disease↗
CD2 rescues T cells from T-cell receptor/CD3 apoptosis: a role for the Fas/Fas-L system.
Anti-CD3 monoclonal antibodies (MoAbs) and glucocorticoid hormones induce apoptosis in immature thymocytes and peripheral T lymphocytes. This process is inhibited by a number of growth factors, including interleukin-2 (IL-2), IL-3, and IL-4, as well as by triggering of the adhesion molecule CD44, which would indicate that signals generated by membrane receptors can modulate the survival of lymphoid cells. To investigate whether triggering of CD2 may also affect apoptosis in lymphoid cells, we analyzed the effect of stimulation with anti-CD2 MoAbs on T-cell apoptosis induced by two stimuli, anti-CD3 MoAbs and dexamethasone (DEX), using a hybridoma T-cell line and a T-helper cell clone. The results show that CD2 engagement decreased anti-CD3 MoAb-induced apoptosis, but did not influence DEX-induced cell death. Furthermore, the decrease appeared to be related to the expression of Fas/APO-1 (CD95) and Fas-ligand (Fas-L). In fact, we show that CD2 stimulation inhibits apoptosis by preventing the CD3-induced upregulation of Fas and Fas-L in a Fas-dependent experimental system. These data suggest that a costimulatory molecule may control a deletion pathway and may therefore contribute to the regulation of peripheral tolerance.
Animals↗
Orthoclone OKT3 for graft failure after allogeneic bone marrow transplantation: a case report.
Orthoclone OKT3 has been used in the prophylaxis or treatment of acute graft-versus-host disease (GVHD). No previous report of Orthoclone OKT3 in the treatment of marrow allograft failure has been found. Here a case of chronic myelocytic leukemia is presented where the patient received unrelated bone marrow transplantation and developed late graft failure. After failing all other immunosuppressive agents, marrow allograft was successfully rescued by the use of Orthoclone OKT3.
Acute Disease↗
Prognostic factors and early resumption of cyclosporin A in renal allograft recipients with thrombotic microangiopathy and hemolytic uremic syndrome.
Biopsy-proven thrombotic microangiopathy (TMA) was found in 22 of 436 (5%) renal transplant recipients, with similar incidence in recipients of cadaver or living related allografts. All patients with TMA presented different degrees of severity of the hemolytic uremic syndrome (HUS). Prognosis was poor when HUS occurred shortly after transplant in recipients of cadaveric kidneys (55% graft loss). It was more favorable when HUS occurred later in the post-transplant course or in recipients with allografts from living related donors, irrespective of time of occurrence. Other factors such as extent of TMA, degree of thrombocytopenia, hemolysis or renal dysfunction were not predictive of graft loss. Cyclosporine was resumed in 14 of 16 recipients shortly after clinical recovery without recurrence of HUS. In conclusion, HUS carries poor prognosis when occurring shortly after transplant in cadaver kidney recipients. Once the graft function improves, cyclosporine can be safely resumed.
Adult↗
Artificial-capillary-system development of human alloreactive cytotoxic T-lymphocytes that lyse brain tumours.
The production of alloreactive cytotoxic T-lymphocytes (CTL) for therapy of recurrent brain tumours was performed in the CELLMAX artificial capillary system composed of cell-culture modules containing cellulose acetate or cuprammonium rayon hollow fibres. Lymphocytes, obtained from the brain-tumour patient to be used for sensitization, were stimulated with OKT3 (anti-CD3) and interleukin-2 (IL-2) and inoculated into the extracapillary space of artificial capillary modules. For allogeneic CTL production, the expanded patient lymphocytes were harvested, irradiated and placed into a second artificial capillary system with allogeneic lymphocytes from a healthy donor. In a one-way mixed lymphocyte reaction, CTL developed in the presence of low-concentration IL-2 (60 i.u. of IL-2/ml). In 18-21 days the cell preparation usually displayed a predominantly CD3+, CD8+ phenotype, which consorted with the dual-labelled CD8/CD11a markers used to identify CTL. Chromium (Cr)-release assays demonstrated lysis of patient tumour in relation to allogeneic glioma; the response observed in cold-target-inhibition assays confirmed lysis of the relevant tumour by the CTL.
Antibodies, Monoclonal↗
Activation of resting T cells against the CA 72-4 tumor antigen with an anti-CD3/CA 72-4 bispecific antibody in combination with a costimulatory anti-CD28 antibody.
The poor prognosis of advanced gastric carcinoma requires new therapeutic approaches. Among these, the specific activation of resting lymphocytes by bispecific antibodies may be promising. Here we describe the generation and function of a bispecific monoclonal antibody (bi-mab) with specificity for CD3 and for the tumor antigen CA72-4 (TAG72) on various gastrointestinal tumors. We established a hybrid/hybridoma by somatic fusion of two hybridoma lines secreting antibodies against CA72-4 and CD3 respectively and characterized its bimab OKT3/B72.3. In combination with costimulatory anti-CD28 antibodies resting peripheral lymphocytes could be activated specifically by bi-mab OKT3/B72.3 with T cell proliferation and IL-2 secretion. The bi-mab OKT3/B72.3 could also trigger the cytotoxicity of these T cells toward, CA72-4+ cells in vitro. Our results indicate, that bi-mab OKT3/B72.3 in combination with an anti-CD28 mab can redirect T cell cytotoxicity specifically against CA72-4+ tumor cells implicating a novel strategy for the specific immunotherapy of CA72-4+ tumors.
Animals↗
Experimental hepatitis and role of cytokines.
Activated T lymphocytes appear to be responsible for liver damage in chronic active hepatitis and autoimmune liver disease. We described three experimental mouse models of T cell dependent liver injury. D-galactosamine (GalN)-sensitized mice challenged with either T cell activating anti-CD3 monoclonal antibody (mAb) or with the superantigen staphylococcal enterotoxin B (SEB) developed severe liver injury characterized by internucleosomal DNA fragmentation as well as by histological hallmarks of hepatocyte apoptosis, both preceding the increase of plasma transaminases. Administration of the T cell mitogen concanavalin A (Con A) to unsensitized mice also resulted in hepatic apoptosis and the ensuing necrosis. Anti-CD3 mAb as well as SEB or Con A induced the release of systemic tumor necrosis factor (TNF), interferon gamma (IFN gamma), and various other cytokines. Passive immunization against TNF or pretreatment with immunosuppressive drugs such as cyclosporin A, FK 506 or dexamethasone protected mice from liver injury. T lymphocytes were identified as effector cells of Con A in vivo i) by proof of resistance of athyrnic nude mice against Con A and ii) by restoration of susceptibility in nude by lymphocyte transfer from control mice. Moreover, antibody-dependent depletion of CD4+ T cells fully protected against Con A, whereas depletion of CD8+ T cells failed to prevent liver injury. These results indicated that cytokines released following T helper cell activation rather than cytotoxic T cells mediated liver injury. We recently found that IFN gamma is also a critical mediator of Con A-induced hepatic damage. In conclusion, these T cell-dependent models of inflammatory liver injury allow the investigation of basic principles of hepatic disorders associated with T cell activation and infiltration as well as pharmacological in vivo studies for the development of hepatoprotective drugs.
Animals↗
Graft outcome in cadaver renal transplants treated with full-dose cyclosporine induction without antibody, irrespective of graft function.
Cyclosporine (CSA) induction has been shown to prolong delayed graft function which in turn may compromise graft outcome. In this study we report our experience with full-dose CSA induction without antibody treatment irrespective of graft function and stress the importance of achieving therapeutic CSA levels in the early post-transplant period. The records of 293 first cadaver renal transplant recipients who were transplanted between January 1992 and December 1995 were reviewed. Patients were divided into those who had immediate graft function (IGF, n = 197) and the ones who had delayed graft function (DGF, n = 96). Twenty-six (13%) patients in the IGF group and 27 (28%) patients in the DGF group experienced at least one episode of acute rejection (AR), (P = 0.002). Patient and graft survival rates at 1, 2 and 5 yr were similar in the IGF and DGF groups. Cox regression analysis revealed that the absence of both DGF and AR was independently associated with a 0.44 times lower risk of graft failure (P = 0.06), whereas AR without DGF was associated with a 1.9 times increased risk of graft failure (P = 0.02). DGF, with or without AR, did not affect the risk of graft failure. Logistic regression analysis showed that DGF was associated with a 3.6 times higher risk-of AR (P = 0.003). A non-traumatic cause of donor death and preservation time > 24 h were associated with 1.9 and 2.4 times higher risks of DGF (P = 0.01, P = 0.08), whereas female donor gender reduced the risk of DGF by 0.6 (P = 0.1). In conclusion, our results suggest that full-dose CSA induction with achievement of therapeutic target levels in the early post-transplant period is associated with an acceptable graft outcome. Graft outcome was not compromised by delayed function, whereas acute rejection was an independent predictor of graft failure.
Acute Disease↗
Tacrolimus in pancreas transplantation: a multicenter analysis. Tacrolimus Pancreas Transplant Study Group.
This follow-up multicenter analysis is based on 362 pancreas allograft recipients at 14 institutions who were given tacrolimus between 1 May 1994 and 15 November 1995. Three groups were studied: (1) recipients given tacrolimus initially for induction and maintenance therapy (n = 250; 215 without, 35 with, a concurrent bone marrow transplant), (2) recipients who converted to tacrolimus for rescue or rejection therapy (n = 89), and (3) recipients who converted to tacrolimus for other reasons (n = 23). Of 215 recipients without a bone marrow transplant in the induction group, 166 (77%) underwent a simultaneous pancreas-kidney transplant (SPK), 29 (14%) a pancreas transplant alone (PTA), and 20 (9%) a pancreas after previous kidney transplant (PAK). Initial antibody therapy was given to 185 (86%) recipients. All 215 received tacrolimus and prednisone; 202 (94%) also received azathioprine (AZA) and 11 (5%) mycophenolate mofetil (MMF). The most common side effects of tacrolimus were neurotoxicity in 21%, nephrotoxicity in 21%, gastrointestinal (GI) toxicity in 13%, and diabetogenicity in 13% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. Of 89 recipients in the rescue group, 71 (79%) had an SPK, 11 (13%) a PTA, and 7 (8%) a PAK. Before conversion, all had been on cyclosporine (CsA)-based immunosuppression; 74% of them had 2 or more rejection episodes previously. The most common side effects were nephrotoxicity in 27%, neurotoxicity in 26%, GI toxicity in 18%, and diabetogenicity in 8% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. In the induction group patient survival at 1 yr was 98% for SPK, 79% for PTA, and 100% for PAK recipients. According to a matched-pair analysis, pancreas graft survival for SPK recipients at 1 yr was 88% with tacrolimus vs. 73% with CsA (p = 0.002); for PTA recipients, 68% vs. 70% (p > 0.35); and for PAK recipients, 85% vs. 65% (p = 0.13). Graft loss from rejection was not different with tacrolimus vs. CsA in all 3 pancreas recipient categories. At 1 yr, 17% of recipients had converted from tacrolimus to CsA for diabetogenicity, nephrotoxicity, or rejection; 23% had converted from AZA to MMF. The incidence of post-transplant lymphoma was < 2%. In the rescue group, patient survival rates at 1 yr were 96% for SPK, 100% for PTA, and 86% for PAK recipients (p < 0.08). Pancreas graft survival at 1 yr was 89% for SPK, 58% for PTA, and 69% for PAK recipients (p = 0.004). Graft loss from rejection was significantly lower for SPK vs. PTA or PAK recipients. At 1 yr, 20% of recipients had reconverted from tacrolimus to CsA for rejection, neurotoxicity, or nephrotoxicity; 19% had converted from AZA to MMF. There were no post-transplant lymphomas in the rescue group. This follow-up multicenter analysis shows that tacrolimus after pancreas transplantation is associated with high graft survival rates when used for induction and with high graft salvage rates when used for rescue therapy. The rate of graft loss from rejection is low in all 3 pancreas recipient categories. The overall incidence of new-onset insulin-dependent diabetes mellitus is < 1%, as is the incidence of post-transplant lymphoma. Converting from tacrolimus to CsA and, in patients on tacrolimus, from AZA to MMF, is safe; interchangeable use of drugs appears to be of immunologic benefit. To determine the best immunosuppressive regimen after pancreas transplantation, a prospective randomized study comparing tacrolimus and MMF vs. Neoral plus MMF is mandatory.
Adult↗
Treatment of steroid-resistant and recurrent acute cardiac transplant rejection with a short course of antibody therapy.
The purpose of this study was to assess the efficacy of short courses of OKT3 and ATG, respectively, for steroid resistant or recurrent acute allograft cardiac rejection (AR). Between June 1988 and March 1994, 101 heart transplant patients were treated with a quadruple sequential immunosuppression protocol (ATG, azathioprine, CsA, and prednisone). AR was diagnosed by endomyocardial biopsy (EMB), and patients with scores > 2 (ISHLT) received pulse methylprednisolone, 500 mg i.v. on 3 consecutive days. In cases of steroid-resistant or recurrent AR, OKT3 (5 mg/d) or ATG (1.5-2.5 mg/kg/d), was administered for 5-7 d instead of the usual 10-14 d course. OKT3 (17 courses; 10 steroid resistant, 7 recurrent AR; 5.3 +/- 0.7 doses) was given to 16 patients (4F/12M, 45 +/- 11 yr), 29-269 d after transplantation. ATG (8 courses; 5 steroid resistant, 3 recurrent AR; 4.9 +/- 0.6 doses) was given to 8 patients (1F/7M, 53 +/- 7 yr), 23-503 d after transplantation. Successful treatment of AR with a score < 2 at the first and second EMB after treatment was 88% and 88% with OKT3, and 87.5% and 100% with ATG, respectively. Throughout follow-up (50 +/- 22 months after OKT3; 49 +/- 28 months after ATG), there was a trend towards lower incidence of subsequent AR after ATG (25% vs. 69%, P = 0.09), and similar incidence of infections, graft atherosclerosis and mortality. No cases of lymphoproliferative disorder were observed. We conclude that short courses of OKT3 or ATG are safe and effective for the treatment of steroid resistant or recurrent AR, with a similar incidence of complications. These results may have cost-effectiveness implications and need to be confirmed in a randomized study.
Acute Disease↗
Induction immunosuppressive therapy is associated with a low rejection rate after liver transplantation.
Despite advances in immunosuppression, allograft rejection occurs frequently after liver transplantation. The use of induction therapy with cytolytic antibodies may decrease the frequency of rejection in liver transplant recipients, but may also increase the rate of cytomegalovirus (CMV) infection. It has been our center's strategy to use induction therapy in our liver transplant recipients. To determine the outcome of our strategy, we retrospectively reviewed all liver transplants performed in the first 5 yr of our liver transplant program. The frequency of acute rejection in the first year after liver transplantation was only 34% in patients who received induction therapy. The type of induction therapy antibody did not affect the rejection rate. Clinically significant CMV infection (requiring treatment) occurred in 22% of patients. These results suggest that use of induction therapy with cytolytic antibodies does not lead to a high incidence of CMV infection and decreases the incidence of rejection after liver transplantation.
Acute Disease↗