Immunological tolerance

New immunosuppressive agents have significantly improved early survival after organ transplantation for patients with end-stage organ failure. However, a major problem in transplantation is continued to be graft rejection. Chronic allograft rejection threatens the long-term survival of organ transplant recipients. Therefore, induction of donor specific tolerance is very important for improving long-term survival after transplantation. The costimulatory pathways are crucial in regulating T cell activation and donor specific tolerance. The costimulatory pathways are potential therapeutic targets for inducing donor specific tolerance and improving long-term survival after transplantation.     

Gazing into a crystal ball to predict kidney transplant outcome

Kidney transplantation is the optimal therapy for end-stage kidney disease but requires lifelong immunosuppression. Despite improvements in immunosuppression regimens that have reduced rates of acute transplant rejection, long-term allograft survival remains suboptimal. More than 50% of transplanted kidneys from deceased donors fail within 10 years. In order to improve long-term outcomes, physicians need to better understand mechanisms underlying transplant rejection and tolerance in humans. They also need biomarkers that differentiate patients likely to maintain excellent and stable allograft function from recipients at risk of losing their transplants. By studying kidney transplant recipients at high risk for graft loss and rare, spontaneously tolerant kidney transplant recipients, researchers reporting in 3 papers in this issue of the JCI shed new light on these topics.     

Problems in the long-term renal allograft recipient

Despite great improvement in patient and graft survival, the long-term morbidity and mortality in renal transplant recipients are still significant. Cardiovascular disease accounts for much of the mortality in long-term survivors; screening before the transplant procedure and adequate control of hypertension should help improve patient survival. Many of the gastrointestinal complications are due to overimmunosuppression and sepsis. Adequate management must include withdrawal of all immunosuppressive medications in order to save the patient's life. Liver disease is usually of viral origin; patients with chronic active hepatitis or cirrhosis should remain on dialysis. Chronic rejection is the major cause of graft loss in long-term survivors; it is unresponsive to antirejection treatment and its progression may be mediated by nonimmunologic mechanisms. Correctable problems such as renal artery stenosis and ureteral obstruction should be ruled out before a late deterioration in graft function is disregarded as chronic rejection. Post-transplant diabetes, osteonecrosis, cataracts, and nephrotoxicity are directly related to the various immunosuppressive drugs currently used. The lowest dose compatible with graft acceptance should help reduce the incidence of these nonfatal but significant complications. Recurrence of disease is a common histologic finding in many transplant recipients but, except for a few diseases such as HUS, FSGS, and oxalosis, it usually does not lead to graft failure. Successful transplantation restores fertility in many uremic patients. Adequate counseling on contraception is imperative in order to avoid unwanted pregnancies and to delay parenthood for at least 1 year. Current immunosuppressive agents are not teratogenic, no dose adjustments are necessary, and an ill-advised decrease in medication may precipitate a rejection episode. Premature delivery is the major problem in these patients and can be avoided by maintaining adequate graft function and controlling hypertension and infections. It is evident from this review that most of the long-term morbidity and mortality seen in renal allograft recipients are due to overimmunosuppression with sepsis or to side effects of the individual drugs, steroids being a common denominator in almost all cases. New immunosuppressive protocols must aim not only to improve patient and graft survival but also to avoid the many complications that limit the full rehabilitation of these patients.     

The current status of hematopoietic stem cell transplantation for multiple myeloma

Multiple myeloma is often successfully controlled with conventional chemotherapy, but complete remissions are uncommon and cure is rare. High-dose therapy followed by autologous or allogeneic stem cells, employed for the treatment of multiple myeloma in the past 20 years, is promising as a means to increase remission rates and improve survival. Autologous transplants have not always demonstrated survival benefits in randomized studies because most of the patients transplanted relapse, while patients given conventional therapy can receive salvage transplants when they relapse. Efforts to improve the results of autologous transplant include targeted radiation, cytoprotective agents, tandem transplants, or post-transplant immunotherapy. Only allogeneic hematopoietic stem cell transplantation is potentially curative, due to a graft-versus-myeloma effect. While patients who receive either allogeneic or autologous stem cell transplants for multiple myeloma have similar 3-5 year survival, only allograft recipients appear to enjoy long-term disease-free survival. High transplant-related mortality associated with allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative modality. Strategies designed to improve the therapeutic index of allografts include the use of nonablative conditioning regimens, peripheral blood cells rather than bone marrow, graft engineering, and targeted conditioning therapies such as bone-seeking radioisotopes.     

Why do we need biomarkers in solid organ transplantation

Immunosuppressive therapy is administered to all solid organ transplant recipients to help prevent acute rejection and the loss of allograft function. Adequate immunosuppression is a delicate balance between rejection rates and chronic allograft dysfunction on the one hand and immunological and nonimmunological side effects on the other hand. The general strategy is to minimize the toxicity associated with triple immunosuppressive regimens and possibly enhance long-term allograft survival without compromising short-term allograft survival. There are no criteria that enable the clinician to predict who will do well with the decrease or complete avoidance of immunosuppression. It becomes more and more clear that randomized controlled trials will not be able to solve the problem of defining the optimal immunosuppression for a given individual. The most promising road to achieve this goal and to improve chronic allograft survival may be personalized immunosuppression guided by biomarkers complementary to conventional drug monitoring strategies.     

Choice of antibody immunotherapy influences cytomegalovirus viremia in simultaneous pancreas-kidney transplant recipients

OBJECTIVE: Simultaneous pancreas-kidney (SPK) transplantation in type 1 diabetic patients requires immunotherapy against allo- and autoreactive T-cells. Cytomegalovirus (CMV) infection is a major cause for morbidity after transplantation and is possibly related to recurrent autoimmunity. In this study, we assessed the pattern of CMV viremia in SPK transplant recipients receiving either antithymocyte globulin (ATG) or anti-CD25 (daclizumab) immunosuppressive induction therapy. RESEARCH DESIGN AND METHODS: We evaluated 36 SPK transplant recipients from a randomized cohort that received either ATG or daclizumab as induction therapy. Patients at risk for CMV infection received oral prophylactic ganciclovir therapy. The CMV DNA level in plasma was measured for at least 180 days using a quantitative real-time PCR. Recipient peripheral blood mononuclear cells were cross-sectionally HLA tetramer-stained for CMV-specific CD8(+) T-cells. RESULTS: Positive CMV serostatus in donors was correlated with a higher incidence of CMV viremia than negative serostatus. In patients at risk, daclizumab induction therapy significantly prolonged CMV-free survival. CMV viremia occurred earlier and was more severe in patients with rejection episodes than in patients without rejection episodes. CMV-specific CD8(+) T-cell counts were significantly lower in patients developing CMV viremia than in those who did not. CONCLUSIONS: Despite their comparable immunosuppressive potential, daclizumab is safer than ATG regarding CMV infection risk in SPK transplantation. ATG-treated rejection episodes are associated with earlier and more severe infection. Furthermore, high CMV-specific tetramer counts reflect antiviral immunity rather than concurrent viremia because they imply low viremic activity. These findings may prove valuable in the discussion on both safety of induction therapy and recurrent autoimmunity in SPK and islet transplantation.     

Management of the kidney transplant recipient

The short-term outcomes of kidney transplant recipients have improved dramatically in the past 20 years, in large part resulting from the availability of more potent immunosuppressive drugs capable of preventing or treating acute allograft rejection. Ironically, side effects from these same immunosuppressants play a role in the long-term morbidity and mortality of this patient population. As kidney transplant recipients survive for longer periods of time with functioning allografts, primary care physicians will likely become more involved in their management, mandating at least a basic understanding of immunosuppression and its complications.     

New developments in immunosuppressive therapy in renal transplantation

The introduction of new immunosuppressive agents and protocols has improved outcomes for renal transplant recipients by decreasing the risk of rejection and by increasing the function and lifespan of the allograft. This article reviews the major changes in the combinations of therapies used: calcineurin inhibitors, target of rapamycin inhibitors, mycophenolate mofetil, non-depleting monoclonal versus depleting monoclonal and polyclonal antibodies for induction and increasing emphasis on protocols for reduction or avoidance of steroids and calcineurin inhibitors. The new agents with novel immunological targets such as anti-CD40 ligand, LEA29Y, FTY720, anti-CD20 (rituximab, Rituxan, Mabthera) and anti-CH52 (alemtuzumab, Campath), which are under development but have yet to survive the rigors of clinical trials are also discussed. In the presence of low early rejection rates, immunosuppressive therapy is setting new goals such as better graft function (glomerular filtration rates), reduction in adverse effects such as hypertension, hyperlipidaemia and drug toxicity and, above all, the prevention of late graft deterioration.     

Delayed wound healing with sirolimus after liver transplant

OBJECTIVE: To report 3 separate cases of wound dehiscence in liver transplant recipients receiving sirolimus for immunosuppressive therapy. CASE SUMMARIES: Three patients who had received liver transplants experienced a delay in wound granulation and healing after being placed on an immunosuppressive regimen containing sirolimus and steroids. Each patient was admitted and treated for wound dehiscence, at which time sirolimus was discontinued. When other immunosuppressive agents were substituted for sirolimus, each incisional wound granulated and closed without complication. DISCUSSION: Sirolimus is an important adjunctive immunosuppressant used to prevent acute rejection episodes in patients who have undergone transplant, particularly when nephrotoxic effects from first-line calcineurin inhibitors become problematic. The unique ability of sirolimus to inhibit smooth muscle cell proliferation and intimal thickening by blocking important growth factors may subsequently become a significant feature to prevent the development of chronic rejection. Theoretically, by this same mechanism, sirolimus may play a role in forestalling wound healing and may even promote dehiscence. CONCLUSIONS: These case reports describe patients who underwent liver transplant who developed wound dehiscence possibly secondary to sirolimus therapy. Although the cases were complicated by acute rejection, wound infections, and comorbidities, wound granulation and healing began after discontinuation of sirolimus. Substitution with another immunosuppressant may be necessary for patients who experience wound dehiscence after transplant.     

Extracorporeal photochemotherapy: a new therapeutic approach for allograft rejection.

Photopheresis (ECP) is a new immunomodulatory therapy in which recipient lymphocytes are treated extracorporeally with 8-methoxypsoralen (8-MOP) and ultraviolet light. The treatment seems to induce an inhibition of both umoral and cellular rejections after transplantation. More than 160 transplanted patients have been treated with ECP (107 heart, 30 kidney, 24 lung and I liver) in different studies. Indication for ECP included acute rejection, recurrent/refractory rejection, prophilaxis of rejection, need of reducing standard immunosuppression. Patient survival is satisfactory. Only one study where ECP was used as the last therapeutic resource in very compromised patients shows a high rate of mortality. On the contrary, when ECP was used earlier after the failure of a first immunosuppressive line the outcome was better with a very low mortality. An hystological resolution of acute rejection is reported in 89% of cardiac transplant patients. The rate of response is similar even in the other transplanted patients treated with ECP. A better control of alloreactivity has been also reported in both cardiac and renal transplant patients with recurrent rejection. In renal allograft the treatment induces a reduction of both lymphocytes and monocytes infiltrate and downregulates the expression of HLA-DR and integrins ICAM-1 and VCAM-1 on tubular cells. Markers of fibrogenesis such as TGFbeta1 and ASMA are only moderately reduced with a more focal pattern of distribution in the post-ECP specimens. The optimal schedule and the length of treatment are still unclear and probably a patient-tailored treatment is needed at least in responder patients. ECP is effective for patients resistant to conventional treatments, particularly when it is started early. This beneficial effect is obtained without the complications typically encountered with immunosuppressive regimens used to control rejection.     

Cardiac transplantation: a review for critical care nurses

Advances in immunology, immunosuppressive therapy, and preservation techniques have contributed to making cardiac transplantation an accepted therapy for end-stage heart disease. One-year survival rates now exceed 90% at some transplant centers. However, serious complications, such as infection, rejection, coronary artery disease, and malignancies, continue to plague long-term survival rates in this patient population. Balancing the immune system between infection and rejection requires the special expertise of experienced cardiologists and immunologists. An improved understanding of the immune system promises to increase long-term survival rates of cardiac transplant recipients. Critical care nurses require special assessment skills to meet the demanding challenges of cardiac transplant recipients in the immediate postoperative period. The impact of cardiac denervation, immunosuppression, and the risk for acute rejection add a different perspective for nursing interventions in the critical care environment. With mortality rates remaining at 8 to 10% for the first month following cardiac transplantation, the skill of critical care nurses is crucial to decreasing morbidity and increasing survival during the acute perioperative period.     

New developments in immunosuppressive therapy in renal transplantation

The introduction of new immunosuppressive agents and protocols has improved outcomes for renal transplant recipients by decreasing the risk of rejection and by increasing the function and lifespan of the allograft. This article reviews the major changes in the combinations of therapies used: calcineurin inhibitors, target of rapamycin inhibitors, mycophenolate mofetil, non-depleting monoclonal versus depleting monoclonal and polyclonal antibodies for induction and increasing emphasis on protocols for reduction or avoidance of steroids and calcineurin inhibitors. The new agents with novel immunological targets such as anti-CD40 ligand, LEA29Y, FTY720, anti-CD20 (rituximab, Rituxan?, Mabthera?) and anti-CH52 (alemtuzumab, Campath?), which are under development but have yet to survive the rigors of clinical trials are also discussed. In the presence of low early rejection rates, immunosuppressive therapy is setting new goals such as better graft function (glomerular filtration rates), reduction in adverse effects such as hypertension, hyperlipidaemia and drug toxicity and, above all, the prevention of late graft deterioration.     

HA-ving lymphatics improves lung transplantation

Lung allografts are prone to rejection, even though recipients undergo aggressive immunosuppressive therapy. Lymphatic vessels serve as conduits for immune cell trafficking and have been implicated in the mediation of allograft rejection. In this issue of the JCI, Cui et al. provide compelling evidence that lymphatic vessel formation improves lung allograft survival in a murine transplant model. Moreover, their data suggest a potential mechanism for the beneficial effects of lymphatics that does not involve immune cell or antigen transport. Together, the results of this study provide new insight into the role of lymphatic vessels in transplant tolerance.     

血浆置换与免疫球蛋白高敏受者脱敏治疗肾移植

背景：高敏受者肾移植前应用静脉注射免疫球蛋白尚无统一方案,而国内应用较少。目的：探讨采用血浆置换联合静脉注射免疫球蛋白干预的方法,对肾移植高敏受者进行脱敏治疗的可行性及效果分析。方法：28例肾移植患者进行人类白细胞抗原交叉配型,并进行脱敏及血浆置换联合静脉注射免疫球蛋白,观察排斥反应发生率和移植肾存活时间及功能。结果与结论：28例脱敏患者均未发生超急性排斥反应,9例（32%）发生急性排斥反应,其中5例（18%）为急性体液性排斥,所有排斥反应均逆转。平均随访（50±24）个月,移植后1和2年平均血肌酐分别为（112.18±17.20）和（129.78±36.52）μmol/L。移植肾12和48个月年存活率分别为95.0%和78.0%。提示采用血浆置换联合静脉注射免疫球蛋白能有效地对高敏受者进行脱敏治疗,移植后急性体液性排斥发生率高是该方案的主要问题,随访表明近期效果可以,远期效果有待观察。     

The current state of pancreas transplantation

The first pancreas transplant in 1966 demonstrated that a pancreas allograft could reestablish euglycemia independent of exogenous insulin in patients with type 1 diabetes mellitus. Early outcomes were poor, and application of the procedure was limited. In the 1980s, innovations in immunosuppression therapy and surgical management of pancreatic exocrine secretions combined with careful candidate selection resulted in dramatic improvements in patient and graft survival. In the 1990s, the incorporation of additional new anti-rejection agents into immunosuppression protocols resulted in a further decrease in the incidence of acute rejection, affording more freedom in surgical management of exocrine drainage. The vision for the future of transplantation for the treatment of diabetes is focused on the percutaneous infusion of pancreatic islets, thus eliminating the need for surgical revascularization of a pancreas allograft, yet reestablishing regulation of glucose metabolism.     

Use of lymphoplasmapheresis or plasmapheresis in the management of acute renal allograft rejection

Several recent reports have documented the value of intensive plasmapheresis as an adjunct to standard immunosuppressive therapy for patients suffering acute renal allograft rejection. We have treated four rejection episodes in three patients with intensive plasmapheresis and two rejection episodes in two additional patients with intensive lymphoplasmapheresis. Five of six rejection episodes were reversed, and four of the five patients treated have retained functioning grafts for follow-up periods ranging from 4 months to 3 years. Previous investigators have reported encouraging results using plasmapheresis, and we believe our experience supports the requirement for further controlled studies with this procedure. Moreover, we note that no previous work has been described with lymphoplasmapheresis and suggest that removal of lymphocytes, in addition to plasma, may further augment immunosuppression in the treatment of renal allograft rejection.     

RATG: implications for nursing care in organ transplantation

Proper immunosuppression is a key element determining the survival of patients undergoing organ transplantation. RATG is one of several immunosuppressive agents available for use. Nurses need to recognize the unique challenges that RATG poses for patient and dosage preparation, along with those affecting its administration and post administration. Doing so can effectively aid the transplanted patient in achieving optimal immunosuppression with the least amount of unpleasant effects. The hospital stay for a transplant patient can be very frustrating and exhausting. Nursing interventions that limit these effects can foster a more desirable patient experience.     

Cure of cryptococcal infection during continued immunosuppressive therapy

Cryptococcus neoformans is a significant pathogen in immunosuppressed patients. In renal transplant recipients receiving prednisone, the development of cryptococcosis is associated with a poor prognosis. When such patients develop cryptococcosis they pose a particularly difficult clinical dilemma since withdrawal of prednisone, to facilitate cure of their fungal infection, may predispose to loss of their transplanted kidney. We report our experience with cryptococcal infection in 13 renal transplant patients. In 11 of these patients maintenance immunosuppression was cautiously continued to preserve allograft function. The results of our study suggest that maintenance immunosuppressive therapy may be continued throughout the period of antifungal therapy and does not preclude eradication of the infecting organisms. Our experience indicates that the prognosis for the renal transplant patient who has cryptococcosis can be improved.     

Prevention trumps treatment of antibody-mediated transplant rejection

Belying the spectacular success of solid organ transplantation and improvements in immunosuppressive therapy is the reality that long-term graft survival rates remain relatively unchanged, in large part due to chronic and insidious alloantibody-mediated graft injury. Half of heart transplant recipients develop chronic rejection within 10 years — a daunting statistic, particularly for young patients expecting to achieve longevity by enduring the rigors of a transplant. The current immunosuppressive pharmacopeia is relatively ineffective in preventing late alloantibody-associated chronic rejection. In this issue of the JCI, Kelishadi et al. report that preemptive deletion of B cells prior to heart transplantation in cynomolgus monkeys, in addition to conventional posttransplant immunosuppressive therapy with cyclosporine, markedly attenuated not only acute graft rejection but also alloantibody elaboration and chronic graft rejection. The success of this preemptive strike implies a central role for B cells in graft rejection, and this approach may help to delay or prevent chronic rejection after solid organ transplantation.     

Complications after cardiac transplantation. The role of immunosuppression

Increased numbers of cardiac transplantations are being performed as a therapeutic option for end-stage cardiac disease. Immunosuppressive therapy combining multiple drugs to prevent rejection is essential to the success of this procedure. Although the patient's primary problem of heart failure is alleviated by a successful transplant, the secondary effect of immunosuppression causes many potential problems for this patient population. Infection from common pathogens or opportunistic microorganisms is the primary complication causing death in the post-transplant patient. Bacterial, viral, fungal, or parasitic infection may ensue during the postoperative period. Life-long immunosuppressive therapy places the patient at continuous risk for the development of infection. Nurses play an important role in the management of the cardiac transplant patient. A thorough knowledge of normal immune system function and the specific actions of each immunosuppressive drug on the immune system function is a prerequisite for providing care for these patients. Continuous monitoring of the patient to detect the signs and symptoms of infection or other side effects of the drugs is part of the nurse's role in caring for these patients. Maintenance of the patient's nonspecific host defenses is supported by specific nursing actions. In preparation for the life-long effects of the drugs, education of the patient and family regarding the implications of therapy with immunosuppressive agents is a crucial nursing function for the successful management of the cardiac transplant patient.