Additional Immunosuppressive Agents Research Articles

Statement of current majority practices in graft-versus-host disease prophylaxis and treatment in children.

Great variations exist in the prophylaxis and treatment of GVHD in children undergoing allogeneic stem cell transplantation (SCT). The EBMT Working Party Paediatric Diseases (EBMT-WP PD) and the International BFM Study Group--Subcommittee Bone Marrow Transplantation (IBFM-SG), aimed at evaluating current local standards in the prevention and treatment of GVHD and steps which can be taken to achieve a uniform policy for the individual methods. Several conferences with their members assessed practices which are mainly applied or under investigation in children and identified where additional information is needed. For prevention of GVHD, the majority of the paediatric centres prefer CsA +/- MTX. Addition of folinic acid to MTX was considered for reduction of side-effects. During treatment of acute GVHD most centres administer prednisolone and whole blood level-adjusted CsA as medications of first choice. In cases of poor or no response to this therapy, additional immunosuppressive agents such as ATG, mycophenolate-mofetile and tacrolimus are being increasingly used. The treatment of chronic GVHD usually consists of various combinations of prednisolone and CsA. In severe cases, extracorporeal photopheresis, psoralene-UVA (PUVA) and thalidomide are administered.

Factors predicting the long-term success of maintenance cyclosporine monotherapy after kidney transplantation.

The theoretical aim of maintenance cyclosporine monotherapy (mCsA) after kidney transplantation is to reduce the incidence of the metabolic complications of corticosteroids and to minimize the adverse effects of excessive long-term immunosuppression. This study was performed in low-immunological-risk cadaveric kidney transplant recipients to evaluate the risks and benefits of mCsA and the long-term graft survival, and to determine the factors predicting success of this policy. The multicenter retrospective study was conducted in 329 Caucasian patients receiving mCsA out of 728 first cadaveric kidney transplant recipients. The inclusion criteria were: HLA antibodies < or =25%, serum creatinine <200 micromol/L, and no rejection or only one rejection episode. At the end of the study, we compared the group of patients successfully treated with mCsA (successful group) with those requiring additional immunosuppressive agents (unsuccessful mCsA group). Overall patient and graft survival rates for the 728 first cadaveric graft were 92% and 64%, respectively, at 8 years. Out of 329 patients enrolled in mCsA, 240 were maintained on this treatment and 89 were withdrawn (3 deaths, 18 graft losses, 68 functional grafts). The 8-year graft survival in the 329 enrolled mCsA patients was 84%, 95% in the successful mCsA group, and 70% in the unsuccessful mCsA group. Multivariate analysis showed that the factors predicting success of mCsA were: donor age <40 years (P = 0.001), serum creatinine at mCsA initiation <125 micromol/L (P = 0.02), no rejection episode before mCsA initiation (P = 0.005), and glomerulopathy as the primary renal disease (P = 0.001). Numerous kidney transplant recipients with a low immunological risk and good and stable renal function may benefit from discontinuation of prednisone and azathioprine in order to reduce the complications related to these drugs. This therapeutic approach had no adverse impact on the overall long-term graft survival for "low risk" and successful patients.

Effect of low molecular weight heparin on graft vascular disease in the rat cardiac allograft model

HEART transplantation is now an established therapy for irreversible end-stage heart failure. Though cyclosporine (CyA) and other immunosuppressive treatments have reduced the mortality rate of graft transplanted patients, posttransplant chronic graft vascular disease (CGVD) is still a major complication after transplantation. CyA has had minimal impact on CGVD of heart transplant patients. Therefore, new additional immunosuppressive agents are needed to decrease this complication and improve long-term survival. Nitric oxide (NO) is a mediator causing vasodilatation in vascular smooth muscle cells. CyA may not only inhibit proliferation in arterial smooth muscle cells in transplanted cardiac grafts, but it may also be an atherogenic agent, thereby affecting CGVD. Because CyA may inhibit NO synthase (NOS) activity and cause reduction of the production of NO, it may cause hypertension and CGVD in transplanted grafts. On the other hand, heparin may regulate the repair of posttransplant graft coronary arterial injury and arteriosclerosis by inhibiting smooth muscle cell proliferation through increasing NO. Heparin’s inhibitory effect may be partially reversed by NOS inhibitor, which reduces production of NO. Low molecular weight heparin (LMWH), which is depolymerized heparin, has advantages over heparin for improved bioavailability and reduced bleeding. The effect of LMWH on acute rejection and CGVD was studied in a rat cardiac allograft model. The NOS inhibitor, Nv-nitro-Larginine methyl ester (L-NAME), was used to reverse heparin’s effect.

HLA Class II Restriction of Autoreactive T Cell Responses in Pemphigus Vulgaris: Review of the Literature and Potential Applications for the Development of a Specific Immunotherapy

Pemphigus vulgaris (PV) is a life-threatening autoimmune bullous disease of the skin and mucous membranes which requires immunosuppressive therapy, most commonly a combination of glucocorticoids and additional immunosuppressive agents. Since the side effects of long-term immunosuppressive therapy contribute to the poor prognosis of this disorder, there is considerable interest in a more specific treatment of this severe skin disease. PV may serve as a model disease for the development of a specific immunotherapy, because its pathogenesis as well as involved immunogenetic factors are well-characterized. This review focuses on the characterization of autoreactive T cell responses to desmoglein 3 (Dsg3), the autoantigen of PV, that presumably regulate the production of autoantibodies by providing help to the autoreactive B cells. Current knowledge on T cell epitopes of Dsg3 and the HLA class II alleles that restrict Dsg3-specific autoreactive T cell responses, as well as potential applications for a specific immunotherapy of PV, are described.

Noninfectious Posterior Uveitis

Posterior uveitis encompasses a broad range of clinical entities with multiple manifestations. A complete history and physical examination provide diagnostic clues and guide an appropriate laboratory evaluation. An infectious cause should always be considered before instituting therapy. Periocular and systemic corticosteroids are the mainstay of treatment, but additional immunosuppressive agents may be required to control inflammation and minimize side effects. An atypical response to therapy should provoke further testing to rule out a masquerade process. This article reviews the common clinical findings, differential diagnosis, and treatment of posterior uveitis.

EXPERIENCE WITH FK506 IN LIVING-RELATED LIVER TRANSPLANTATION

The new immunosuppressive agent FK506 was used with steroids to treat 22 pediatric patients who received living-related partial liver transplantation. Seventeen recipients survived and 5 died between one and 16 months after transplantation. Three of the 5 patients who died had required intensive care preoperatively. Autopsy findings showed no evidence of rejection. There was no episode of rejection that required retransplantation in any of the patients. Liver allograft dysfunction, which was suspected to be a rejection response, was encountered in 2 recipients with ABO-nonidentical but compatible grafts. However, their clinical and biochemical findings were ameliorated upon steroid pulse therapy or upon augmented FK506 administration without additional potent immunosuppressive agents. Steroid treatment has been discontinued in all surviving patients at 1-9 months after transplantation. Infectious complications encountered in 9 patients included 2 bacterial, 5 viral, and 2 fungal infections. One recipient died of fungal pneumonia. Abnormal increase of serum creatinine level was confined to the complicated patients. Hypertension was a temporary adverse reaction in the early postoperative period, and only one patient needed an antihypertensive drug at 2 months after transplantation. Acute pancreatitis with hyperamylasemia was observed in one patient who was treated successfully with reduction of FK506 administration. Tremor was observed in 8 patients, itching in 4, insomnia in 2, and vomiting in one. Hirsutism, gingival hypertrophy, and lymphoma were not observed. FK506 was highly effective in living-related partial liver transplantation not only in terms of immunosuppressive potential but also because it produced fewer adverse effects.

HEPATIC DYSFUNCTION FOLLOWING T-CELL-DEPLETED ALLOGENEIC BONE MARROW TRANSPLANTATION

We reviewed the medical records of 97 patients undergoing T cell-depleted allogeneic bone marrow transplantation at our institution from 1984 to 1990 to determine the incidence of hepatic dysfunction, including venoocclusive disease of the liver following BMT. All patients received allogeneic marrow that had been purged with monoclonal antibody to the CD6 surface antigen (T12) and rabbit complement as the sole method of graft-versus-host disease prophylaxis. No additional immunosuppressive agents were routinely administered to these patients. Overall, 55% of patients in our series developed two-fold elevations in serum bilirubin, SGOT, or alkaline phosphatase within the first 30 days following BMT. A five-fold elevation in any liver function test was noted in only 19% of patients. Logistic regression analysis revealed that the presence of GVHD, female sex, and administration of amphotericin B all were independently associated with laboratory evidence of hepatic dysfunction. While LFT abnormalities were common in our series, they were generally mild, and the development of VOD was rare. Only three patients (3.1%) fulfilled clinical criteria sufficient to establish a diagnosis of VOD. Among the 86 patients whose ablative regimen consisted of cyclophosphamide (60 mg/kg x2) and total-body irradiation (1200-1400 cGy in 200 cGy fractions), only 1 patient (1.2%) developed VOD. Our experience suggests that patients undergoing allogeneic BMT are at low risk for VOD and other serious hepatic complications when they receive high-dose cyclophosphamide, fractionated TBI, and T cell-depleted marrow without hepatotoxic medications for GVHD prophylaxis.

Neurosarcoidosis

Thirty-five cases of biopsy-proven sarcoidosis with neurologic manifestations are reported. Neurosarcoidosis was the presenting symptom in 31% of cases and the only clinical manifestation in 17%. Mean follow-up time was 48 months. Central nervous system involvement was observed in 37% and meningitis in 40% of patients. Other manifestations were cranial nerve palsies (37%), peripheral neuropathy (40%), and myopathy (26%). Multiple neurologic manifestations were present in 51% of cases. All but 4 were treated with corticosteroids. Another immunosuppressive agent or cerebral irradiation was added in 6 and 2 patients, respectively. Complete recovery was observed in 46%, improvement in 46%, 4% remained stable, and 4% worsened. There were no deaths. We advocate treating neurosarcoidosis with corticosteroids as early as possible. If the patient's condition worsens, additional immunosuppressive agents or cerebral irradiation is warranted.

Booster irradiation to the spleen following total body irradiation. A new immunosuppressive approach for allogeneic bone marrow transplantation.

Graft rejection presents a major obstacle for transplantation of T cell-depleted bone marrow in HLA-mismatched patients. In a primate model, after conditioning exactly as for leukemia patients, it was shown that over 99% of the residual host clonable T cells are concentrated in the spleen on day 5 after completion of cytoreduction. We have now corroborated these findings in a mouse model. After 9-Gy total body irradiation (TBI), the total number of Thy-1.2+ cells in the spleen reaches a peak between days 3 and 4 after TBI. The T cell population is composed of both L3T4 (helper) and Lyt-2 (suppressor) T cells, the former being the major subpopulation. Specific booster irradiation to the spleen (5 Gy twice) on days 2 and 4 after TBI greatly enhances production of donor-type chimera after transplantation of T cell-depleted allogeneic bone marrow. Similar enhancement can be achieved by splenectomy on day 3 or 4 after TBI but not if splenectomy is performed 1 day before TBI or 1 day after TBI, strengthening the hypothesis that, after lethal TBI in mice, the remaining host T cells migrate from the periphery to the spleen. These results suggest that a delayed booster irradiation to the spleen may be beneficial as an additional immunosuppressive agent in the conditioning of leukemia patients, in order to reduce the incidence of bone marrow allograft rejection.

Cyclosporine: A New and Promising Immunosuppressive Agent

Cyclosporine is an exciting new agent that has been heralded as a major advance in chemical immunosuppression for organ transplantation. The drug is a potent, reversible suppressant of both humoral and cellular immunity and does not cause myelosuppression. Its mechanism of action appears to be selective for lymphocytes and may interrupt the necessary cellular signals required for proliferation of alloreactive T-cells. In early clinical trials cyclosporine has been shown to ameliorate renal allograft survival. A major concern about its widespread clinical use has been the observed nephrotoxicity and possible development of lymphomas in treated patients. Adverse side effects may be minimized by pharmacologic monitoring of drug levels. Future questions include the ideal dosage schedule, necessity for additional immunosuppressive agents, distinction between nephrotoxicity and rejection, and the precise mode of absorption, accumulation, and metabolism of the drug. Cyclosporine may be considered the prototype of a new generation of immunosuppressive agents that open up new perspectives in the field of immunoregulation. The ability to synthesize the compound may permit future biochemical manipulations to increase the immunobiologic specificity and decrease the toxicity of the drug.

Ocular hypothermia: anterior chamber perfusion.

The anterior chambers of 27 rabbit eyes were perfused at constant pressure with room temperature (25 degrees C) or cooled (11 degrees C) balanced salt solution at constant flow rates of 4.8 ml/min or 8.5 ml/min. Intraocular temperature changes in the anterior chamber, anterior vitreous, mid vitreous, and posterior vitreous and on the retina surface were monitored with an intraocular thermocouple probe. Perfusion of the anterior chamber of the pigmented rabbit eye with cooled fluid significantly reduced the temperature of the anterior chamber and anterior vitreous and even that of the retina. Both an increase in the rate of perfusion and a lowering of the perfusion temperature enhanced the cooling effect. The observed decrease in temperatures returned to approximately normal 4 minutes following the cessation of perfusion.

Cyclosporine: A New and Promising Immunosuppressive Agent

Cyclosporine is an exciting new agent that has been heralded as a major advance in chemical immunosuppression for organ transplantation. The drug is a potent, reversible suppressant of both humoral and cellular immunity and does not cause myelosuppression. Its mechanism of action appears to be selective for lymphocytes and may interrupt the necessary cellular signals required for proliferation of alloreactive T-cells. In early clinical trials cyclosporine has been shown to ameliorate renal allograft survival. A major concern about its widespread clinical use has been the observed nephrotoxicity and possible development of lymphomas in treated patients. Adverse side effects may be minimized by pharmacologic monitoring of drug levels. Future questions include the ideal dosage schedule, necessity for additional immunosuppressive agents, distinction between nephrotoxicity and rejection, and the precise mode of absorption, accumulation, and metabolism of the drug. Cyclosporine may be considered the prototype of a new generation of immunosuppressive agents that open up new perspectives in the field of immunoregulation. The ability to synthesize the compound may permit future biochemical manipulations to increase the immunobiologic specificity and decrease the toxicity of the drug.

CYCLOSPORIN A INITIALLY AS THE ONLY IMMUNOSUPPRESSANT IN 34 RECIPIENTS OF CADAVERIC ORGANS: 32 KIDNEYS, 2 PANCREASES, AND 2 LIVERS

34 patients treated with cyclosporin A received 36 cadaveric organ allografts (32 kidneys, 2 pancreases, and 2 livers). 26 kidneys are still supporting life, 3 after more than a year; the pancreases and livers are also functioning. 20 patients are not receiving steroids, and 15 of these have not had any additional immunosuppressive agents. In these patients infectious complications have not been severe, but a gastroduodenal lymphoma has developed in 1 patient. 6 patients were given 'Cytimun' (a cyclophosphamide derivative) and steroids in addition to cyclosporin A: 5 of these died of infections and 1 also had a lymphoma. 11 patients received additional steroids: 1 of these died from septicæmia and lymphoma. Nephrotoxicity can be avoided by perioperative hydration and forced diuresis. Cyclosporin A is effective on its own and is a very potent immunosuppressive drug. Additional immunosuppressive agents may lead to severe complications.