Modern Immunosuppressive Therapy Research Articles

Autoantibodies

Serologic identification of circulating autoantibodies has proven useful in the diagnosis of patients with autoimmune disorders. In vitro and in vivo [1][1][][2][][3][][4]–[5][5] observations suggest that some autoantibodies are more than just serologic markers; they also participate in the

Tuberculose–pneumocystose : une association à ne pas méconnaître

Modern immunosuppressive therapy may be responsible for toxic, immunologic and infectious pulmonary diseases.We report the case of a 58-year old woman treated for rheumatoid arthritis who received leflunomide, corticosteroids, methotrexate and adalimumab. She developed disseminated tuberculosis, which presented with neurological symptoms (brainstem) and also pneumocystis pneumonia.Modern immunosuppressive therapy used to treat inflammatory disorders in connective tissue diseases and in transplantation may induce new respiratory diseases, new patterns of known respiratory diseases or co-infections that are very seldom seen outside the context of HIV. Pulmonologists, rheumatologists, internists and intensivists should be aware of this new spectrum of diseases whose presentation may be atypical.

Update on transplantation tolerance

The induction of transplantation tolerance has become a major goal, because modern immunosuppressive therapy has not improved chronic rejection rates, and is associated with significant side effects. This article aims to explain the principles of immunological tolerance. Mechanisms of central tolerance involve deletion of self-reactive T cells. Mechanisms of peripheral tolerance are reviewed and also the identification of a subset of regulatory T cells which are characterised by the expression of the transcription factor FoxP3. Interesting recent insights on the role of the ‘anti-inflammatory’ cytokine transforming growth factor β which can ultimately lead to the generation of inhibitory Tregs or inflammatory Th17 cells (CD4 helper T cells which secrete the pro-inflammatory cytokine IL17) are discussed. There are many ways to induce experimental tolerance in animals, however these are difficult to translate tolerance into the clinical context. In addition, standard immunosuppressive agents are calcineurin inhibitors which block T cell activation and IL-2 production. These drugs not only inhibit the activation of effector T cells, but also Tregs, therefore inhibiting Treg driven tolerance induction. Other classes of immunosuppressive drugs should be introduced into the clinic to allow for the possibility of tolerance induction. Strategies to modulate immune responses following transplantation and their potential risks are discussed.

HLA‐matched kidney transplantation in the era of modern immunosuppressive therapy

AbstractBACKGROUNDThe effect of HLA match on renal graft survival has become controversial as has the policy of mandatory sharing of kidneys.METHODWe performed a retrospective analysis of HLA matched (M) and mismatched (MM) kidney transplants in our center. Tacrolimus, mycophenolic acid, and steroids were used as maintenance therapy and basiliximab induction was added for high‐risk patients.RESULTA total of 229 kidney transplants were included with median follow‐up of 5.1 years. The 5‐year death‐censored graft survival by Kaplan‐Meier method was significantly higher in the M group than in the MM group for deceased‐donor kidney transplants (log‐rank, p = .018). This graft survival advantage was detected in patients with a peak panel reactive antibody (PRA) greater than 20% (p = .023), but not in those with a PRA level of less than 20% (p = .32). The graft survival was not statistically different for live donor kidney transplants (p = .077). A mismatched kidney was an independent risk for graft loss (hazard ratio: 2.27, 95% confidence interval: 1.009–5.09, p = .047) and acute rejection was a significant cause of graft loss in mismatched deceased‐donor transplants (p = .035).CONCLUSIONAcute rejection remains a significant cause of graft loss in HLA‐6‐antigen mismatched deceased‐donor kidney transplants. Our data support mandatory sharing of HLA‐matched kidneys in sensitized patients with a PRA level greater than 20%.

Cold Ischemia is a Major Determinant of Acute Rejection and Renal Graft Survival in the Modern Era of Immunosuppression

The aim of our study was to examine, in a recent cohort of kidney transplant recipients who have received modern immunosuppressive therapy, the respective role of cold ischemia time (CIT) and delayed graft function (DGF) on acute rejection (AR) rates and long-term graft survival. We retrospectively reviewed the charts of 611 renal transplantations between 1996 and 2005. Most patients received a calcineurin inhibitor as maintenance therapy, either cyclosporine (43%) or tacrolimus (52%) and 76% of the patients received an antilymphocyte induction therapy. Study endpoints were DGF, first-year AR, and long-term graft survival. Uni- and multivariate analyses were performed to determine factors that may have influenced the study outcomes. DGF was observed in 16.2% of patients. Both older donor age and longer CIT were significant risk factors for DGF. DGF rates were similar whether patients received a calcineurin inhibitor before transplantation or not. AR occurred in 16.5% of grafts during the first year. Independent predictors of AR by multivariate analysis were duration of dialysis, CIT, current panel-reactive lymphocytotoxic antibody more than 5%, and the number of human leukocyte antigen-A, B, and DR mismatches. Each hour of cold ischemia increases the risk of rejection by 4%. With respect to death-censored graft survival, three pretransplant parameters emerged as independent predictors of graft loss: younger recipient age, peak panel-reactive lymphocytotoxic antibody more than 5% and longer CIT. The detrimental effect of CIT on graft survival was entirely because of its propensity to trigger AR. When AR was added to the multivariate Cox model, CIT was no longer significant whereas first-year AR became the most important predictor of graft loss (Hazards ratio, 4.6). Shortening CIT will help to decrease not only DGF rates but also AR incidence and hence graft loss. Patients with prolonged CIT should receive adequate immunosuppression, possibly with antilymphocyte preparations, to prevent AR occurrence.

Association of Elevated Pretransplant sCD30 Levels With Graft Loss in 206 Patients Treated With Modern Immunosuppressive Therapies After Renal Transplantation

Recent reports suggest that high pretransplant serum levels of soluble CD30 (sCD30) are a risk factor for rejections after kidney transplantation. The aim of our study was to elucidate the predictive value of pretransplant sCD30 levels for kidney transplantation outcome in a single-center patient cohort that has been treated with modern immunosuppressive therapies after transplantation. We retrospectively analyzed sCD30 in multiple pretransplant sera from 206 patients, of whom 174 were transplanted with a cadaveric kidney and 32 patients received an allograft from a living donor. Renal function after transplantation was estimated by measuring serum creatinine and by rejection diagnosis. We could demonstrate a statistically significant association between increased pretransplant sCD30 values and graft failures (P=0.005). Receiver operating curve analysis revealed a cutoff value of 124 U/mL pretransplant sCD30. A multivariate analysis confirmed pretransplant sCD30 values >124 U/mL (P=0.011) and rejection episodes (P<0.0001) as independent risk factors for graft loss. Our study revealed a strong correlation between pretransplant sCD30 levels and the incidence of graft failure, but we could not confirm that the development of rejection episodes is correlated with pretransplant sCD30 values.

Alcohol binging causes peliosis hepatis during azathioprine therapy in Crohn's disease

Patients with inflammatory bowel disease have normal life expectancy and, due to modern immunosuppressive therapies, also a normal quality of life. Since mostly young people are affected, their social behaviour suits this environment. Alcohol binging is an increasingly disturbing factor among young people. We describe a patient with Crohn's disease, treated with azathioprine, who developed peliosis hepatis after three epsiodes of alcohol binging. Liver toxicity was not observed previously during the course of the treatment. Azathioprine-induced peliosis hepatis is thought to be idiosyncratic in humans. From animal studies, however, it is clear that hepatic depletion of glutathione leads to azathioprine toxicity to the sinusoidal endothelial cells. Damage of these cells causes peliosis hepatis. Since alcohol binging leads to hepatic glutathione depletion, we conclude that in our patient the episodes of binging have reduced liver gluathione content and therefore this has increased azathioprine toxicity causing peliosis hepatis. The problem of alcohol binging has not yet been addressed in IBD patients undertaking immunosuppressive therapy. This should be reviewed in future considerations regarding patients advice.

Increasing Incidence of Post-Kidney Transplant Anemia in Children

Anemia status at 1-year post-kidney transplant was documented retrospectively in 231 pediatric recipients (mean age: 12.6 +/- 5.0, range: 1.9-20.7 years) at Cincinnati Children's Hospital Medical Center between 1978 and 2003. Anemia was present in 59 (25.5%) patients. The prevalence of anemia has increased in the more recent eras (1978-1985: 7.8%, 1986-1997: 29%; 1998-2003: 32%, p < 0.01). Logistic regression analysis determined that the use of calcineurin inhibitors or impaired allograft function predicted anemia at 1-year post-transplant. Kaplan-Meier analysis showed that children with anemia at 1-year post-transplant had a significantly worse overall allograft survival than children without anemia (p = 0.02). However, when data were analyzed using a Cox proportional hazards model, only lower allograft function at 1-year post-transplant, black race and older era, but not anemia, independently predicted worse graft survival in children. This study suggests that the recent increase in the incidence of anemia post-kidney transplant is related to modern immunosuppressive therapy and that post-transplant anemia is more likely a marker of allograft dysfunction in children rather than its cause.

Clinical Case Notes

Sympathetic ophthalmia is a rare and potentially visually devastating bilateral panuveitis, typically following non-surgical penetrating injury to one eye. Three patients are presented where sympathetic ophthalmia developed after repeated vitreoretinal surgery. Prompt and effective management with systemic immunosuppressive agents permitted control of their disease and retention of good visual acuity in their remaining eye. Vitreoretinal surgery is an important risk factor in sympathetic ophthalmia. Informed consent for vitreoretinal surgery (especially in the re-operation setting) should now include the risk of sympathetic ophthalmia (approximately 1 in 800). Diverse clinical presentations are possible in sympathetic ophthalmia and any bilateral uveitis following vitreoretinal surgery should alert the surgeon to the possibility of sympathetic ophthalmia. Modern immunosuppressive therapy with systemic steroids and steroid-sparing agents such as cyclosporin A and azathioprine have improved the prognosis. This is particularly so in cases where early diagnosis is made and prompt and suitable immunotherapy is commenced.

Long-term follow-up of renal transplantation in children: a Dutch cohort study.

Few data exist on long-term morbidity, overall survival, and graft survival of pediatric renal transplantation. The authors performed a long-term cohort study in all Dutch patients, born before 1979, with onset of end-stage renal disease (ESRD) between 1972 and 1992 at age 0 to 15 years. Data on graft survival and determinants of outcome were obtained by reviewing all medical charts. The health status was assessed by cross-sectional examination of surviving patients. Three hundred ninety-seven transplantations were performed in 231 of all 249 patients, of whom 25 died with a functioning graft. Cardiovascular disease was the most prominent cause of death. Graft survival estimates for all transplantations were 59.2%, 45.3%, 35.4%, and 30.3% at 5, 10, 15, and 20 years, respectively. In comparison with azathioprine, cyclosporine as the immunosuppressant was associated with increased graft survival in retransplantations but not in first transplantations. Cross-sectional examination was performed on 110 patients. In 44 patients, the most recent graft survival exceeded 15 years. Co-morbidity was found in 40% of all patients; motor, hearing, or visual disabilities were found in 19%. Bone disease, headaches, itching, and tremors were the most reported disabling problems. Cyclosporine use was associated with hypertension and a history of epilepsy. Compared with all age-matched Dutch inhabitants, the educational attainment was low, and unemployment and parental dependency were high. The authors' results emphasize the need for reducing cardiovascular disease and metabolic bone disease in pediatric ESRD, a policy toward less toxic antirejection therapy, a more strict treatment of hypertension, and more attention for schooling and social development toward independence.

Corticosteroid elimination in renal transplantation: pro

CLINICAL MANIFESTATION of corticosteroid-related morbidities are protean in scope, and there remains little argument among transplant professionals that their elimination is a worthy goal in managing solid organ transplant recipients. Unequivocal proof that elimination of corticosteroids is superior to long-term corticosteroid therapy has remained a difficult goal to achieve due to a number of barriers. The most salient of these barriers include: (1) lack of accepted, objective parameters for measuring salutary effects of corticosteroid elimination; (2) misinterpretations and misleading conclusions regarding risk of late allograft loss in patients in whom maintenance corticosteroid therapy has been eliminated; (3) design flaws in randomized trials of corticosteroid elimination; (4) failure to assure inadequate maintenance immunosuppression in patients in whom corticosteroids are eliminated; (5) obfuscation of the benefits of elimination of maintenance corticosteroid therapy by treatment of rejection with high-dose corticosteroid therapy; and (6) elimination of corticosteroid therapy at relatively late points in the posttransplant period, beyond which the morbid effects of corticosteroid therapy have already been incurred. An outstanding example of how previous, outdated trials can lead to erroneous conclusions has recently been provided in a published meta-analysis of corticosteroid withdrawal (CSWD) trials. This study actually constituted a rigorous, exhaustive analysis of published corticosteroid withdrawal trials. A total of 10 trials were analyzed, and statistical analysis of risk for graft loss after CSWD was estimated to be 1.38. However, analysis of these studies indicated that the risk of graft loss was not statistically significant in any of these studies, and that the underlying immunosuppression in two of the trials was an inadequately dosed sandimmune version of cyclosporine Neoral. Moreover, the risk in the third study, the CCTAT randomized trial, was largely incurred in African American patients. The inclusion of several trials in which CSWD was performed under outdated immunosuppression obviates the current clinical significance of the author’s conclusions that the risk of graft loss is increased after CSWD. Over the past few years, a number of new, more potent immunosuppressive agents have received regulatory approval including tacrolimus, mycophenolate mofetil, sirolimus, anti-IL-2 receptor antibodies, and thymoglobulin. Data from randomized and nonrandomized trials with these agents has provided cogent evidence that corticosteroid withdrawal is now more easily achieved, and with substantially reduced risks of acute rejection. Moreover, combination therapy with these agents has allowed complete avoidance of maintenance corticosteroid therapy, or, alternatively, elimination at early time points in the posttransplant period (viz, within the first posttransplant month). Finally, recent data has indicated that induction antibody therapy in combination with these new agents may allow complete abrogation of the risk of acute rejection in patients in whom maintenance corticosteroid therapy is eliminated. To date, several trials have been reported where corticosteroid withdrawal or corticosteroid avoidance (CSAV) has been conducted under modern immunosuppressive therapy that includes at least one of the following agents: mycophenolate mofetil, tacrolimus, or sirolimus. These studies have each shown that the risk of moderate acute rejection in primary renal allograft recipients in whom CSWD or CSAV has been been performed has been less than 5%. These data argue strongly that the risk of acute rejection in CSWD is substantially less under modern immunosuppressive therapy, and that older experiences under cyclosporine/ Azathioprine therapy are outdated. In conclusion, a new era has dawned for elimination of corticosteroid therapy from maintenance immunosuppressive regimens in renal transplant recipients. Their use in maintenance anti-rejection therapy is being reduced or eliminated in an increasing number of transplant programs.

Cytokines in Immunity and Allograft Rejection

Cytokines are highly potent regulatory molecules that are secreted by a variety of cells into the local microenvironment. These chemical messengers participate in the activation and regulation of immune function by a variety of mechanisms, including the stimulation and inhibition of cellular proliferation and differentiation. Cytokines also may have chemotactic activity. Six cytokine receptor families have been described, on the basis of their conserved structural features. Many cytokines are classified as proinflammatory cytokines, which promote both innate and adaptive immune responses. Solid-organ transplantation presents several unique challenges to the immune system, and cytokines play an important role in both antigen-dependent and antigen-independent immune recognition. The selective blockade of cytokine-mediated immune responses is a cornerstone of modern immunosuppressive therapy.

Isolation from pig liver microsomes, identification by tandem mass spectrometry and in vitro immunosuppressive activity of an SDZ-RAD 17,18,19,20,21,22-tris-epoxide.

Macrolide immunosuppressive drugs such as tacrolimus (FK506) and sirolimus (rapamycin) are compounds largely used in modern immunosuppressive therapy and considered as powerful immunosuppressive agents. Some of these molecules are still under clinical development as, for example, SDZ-RAD (40-O-(2-hydroxyethyl)rapamycin), an immunosuppressive drug closely related to rapamycin. SDZ-RAD has a molecular mass of 957.57 Da (C53H83NO14) and shares the same common intracellular receptor as tacrolimus, the FK-506 binding protein (FKBP-12). SDZ-RAD exerts its pharmacological effect by binding to a different effector protein, inhibits the S6p 70-kinase and interrupts a different signal transduction pathway than tacrolimus. Both SDZ-RAD and rapamycin are metabolized mainly by the cytochrome P-450 3A4-dependent mixed function oxygenase enzyme system to hydroxylated and demethylated metabolites. We describe here the isolation from pig liver microsomes of a novel SDZ-RAD metabolite identified by electrospray tandam mass spectrometry as a new SDZ-RAD 17,18,19,20,21,22-tris-epoxide metabolite. The in vitro immunosuppressive activity as measured by the mixed lymphocyte reaction is more or less comparable to that of SDZ-RAD, although its pharmacological mode of action may be different from that classically described for rapamycin.

Infections After Organ Transplantation

Over the last ten to fifteen years medical and surgical advances have led to lower rates of infection and infection-related mortality in transplant recipients. Despite these advances, the process whereby one diagnoses and manages infectious problems in transplant patients has become increasingly complex. Evaluation of transplant patients with infections requires a good understanding of the intricacies of modern immunosuppressive therapy and both the typical and atypical clinical manifestations of many conventional and opportunistic pathogens. In particular, it is incumbent upon the clinicians caring for transplant patients to be familiar with the biology of cytomegalovirus and other herpes viruses, and of the prophylactic strategies that have evolved to lessen the burden of disease from these agents. Thorough knowledge is also required of common fungal pathogens and the viruses that cause chronic hepatitis. Transplant patients also should always be evaluated in the temporal context of their transplant operation, because different diseases are prevalent at different times after transplantation. Since immunosuppressive drugs modify the clinical presentation of infections is important to maintain clinical vigilance and attend to even minor new symptoms. This chapter is designed to provide a relatively concise overview of transplant infections for intensivists or other clinicians who encounter transplant patients in their practice. The references encompass much of the classic transplant infectious disease literature; they are included, not only for citation, but as a bibliography for further study.

Sympathetic ophthalmia: visual results with modern immunosuppressive therapy.

Sympathetic ophthalmia is a rare bilateral panuveitis that follows penetrating injury to one eye. The use of systemic corticosteroids has transformed the prognosis, and good acuity in the sympathizing eye can now be achieved. The use of immunosuppressive drugs, such as cyclosporin and azathioprine, in combination with the steroids, allows control of the intraocular inflammation at a much lower steroid dose, with concomitant reduction in the systemic side effects that accompany the use of systemic steroids.

THE PREVALENCE OF HYPERLIPIDEMIA IN RENAL TRANSPLANT RECIPIENTS

To determine the extent of persisting hyperlipidemia in renal transplant recipients receiving modern maintenance immunosuppressive and antihypertensive therapy we compared plasma levels of total and high-density lipoprotein and triglyceride in 275 renal transplant recipients with stable graft function with age- and sex-matched groups from the local general population (n = 4055). Total cholesterol and triglyceride were higher in transplanted patients in all age groups, but the difference was much more striking in women. Plasma levels of HDL cholesterol were similar or slightly lower in transplanted patients. Association with parameters of graft function, immunosuppressive therapy, and antihypertensive therapy were studied within the transplanted population using multiple regression. Total cholesterol was significantly and independently associated with age, sex, diuretic therapy, and urinary protein. In 127/134 (95%) of patients the diuretic was a loop diuretic. None of the other classes of antihypertensive drug was independently associated with serum cholesterol. The only variables significantly associated with HDL cholesterol were sex and the plasma creatinine. Plasma triglyceride was significantly and independently associated with both diuretic therapy and beta-blocker therapy and with age, urinary protein excretion, and plasma albumin. Plasma cholesterol, HDL cholesterol, and triglyceride levels were almost identical in patients receiving triple therapy (cyclosporine 3-5 mg/kg; prednisolone 7-10 mg o.d.; azathioprine 1-1.5 mg/kg) to those in patients receiving conventional immunosuppression (prednisolone 7-10 mg o.d.; azathioprine 2-2.5 mg/kg). Thus these results do not support the existence of a persisting long-term effect of cyclosporine on plasma cholesterol and triglyceride at these doses of the drug. The more striking abnormality of plasma cholesterol and triglyceride in females is unexplained but might be connected with greater sensitivity to low doses of corticosteroids.

Wegener's Granulomatosis — Clinical-Pathologic Correlations and Long-Term Course

Although Wegener's granulomatosis is a relatively well defined clinical-pathologic entity, there are few long-term reports of large numbers of patients followed at a single institution. This has hindered appreciation of the diagnosis, management, and course of the syndrome. We report an analysis of 18 patients followed at one medical center. Delay in treatment can be obviated by awareness of this potential diagnosis in any patient with combined respiratory and renal manifestations. Biopsy of involved respiratory tissue yields a high probability of establishing a specific diagnosis, while biopsy of renal tissue often provides confirmatory evidence of a vasculitic disease process. The initial degree of renal involvement as manifested by serum creatinine, proteinuria, and light microscopic morphology correlates well with eventual prognosis. The availability of modern immunosuppressive therapy and of modalities to treat end-stage renal disease appears to have greatly influenced the course of the disease.