**10.2 Calcineurin inhibitor-free protocols**

Because of the risk of both acute and chronic nephrotoxicity attributed to calcineurin inhibitors, the development of protocols free of these agents is desirable. The use of sirolimus, MMF, and anti-CD25 antibodies has been studied to determine whether graft survival and acute rejection rates can be maintained at the present rates in the absence of calcineurin inhibitors.

Studies in mice have shown that Tregs are antigen-specific and that they regulate peripheral tolerance by producing suppressive cytokines such as IL-10 and TGF-beta. They depend on continuous antigen exposure to stay capable of mediating suppression. Antigen removal

In allograft rejection, direct stimulation of T cells in response to donor-derived antigens presented by donor APCs had been the focus of transplantation research for many years. However, indirect antigen presentation, in which self-APCs present donor peptides in an MHC-restricted fashion is responsible for the induction of antigen-specific Tregs that can directly and indirectly suppress other alloreactive T cells. Although positive costimulation with CD28 appears to be necessary for the development of intrathymically derived Tregs, costimulation blockade with CTLA-4 is required for the development of peripherally

Although tolerance induction may allow for the withdrawal of immunosuppression in the future, at this time, immunosuppressive medications appear to be necessary for the life of

The known toxicity of long-term steroid exposure has prompted the development of steroidfree immunosuppressive regimens. Benefits of the withdrawal or avoidance of steroids include normal growth in children, improved lipid profiles, improved blood pressure, better

The development of cyclosporine prompted attempts to develop steroid-free protocols. Initially, patients were doing well with cyclosporine monotherapy. Over time, 50% of these patients required steroids, usually for episodes of acute rejection. Strong randomized studies are undoubtedly needed to prove both the efficacy and the safety of these protocols. Steroid withdrawal has been used as a strategy to avoid adverse steroid effects in transplanted patients. Recent data show that the risk of rejection is higher in patients withdrawn from steroids on a cyclosporine-based protocol. After tacrolimus became available, protocols with this drug showed that withdrawal of steroids after 6 months was successful 80% of the time. More recently, studies involving rapid steroid withdrawal (over 1-2 wk) in patients taking tacrolimus show similar graft survival rates compared with patients withdrawn after 3-6 months. Although the roles of sirolimus and MMF in steroidfree protocols have yet to be definitively determined, the future looks promising for greater

Because of the risk of both acute and chronic nephrotoxicity attributed to calcineurin inhibitors, the development of protocols free of these agents is desirable. The use of sirolimus, MMF, and anti-CD25 antibodies has been studied to determine whether graft survival and acute rejection rates can be maintained at the present rates in the absence of

reduces the quantity of cells.

acquired suppressor Tregs.

the transplanted organ[33].

use of steroid-free protocols.

calcineurin inhibitors.

**10.2 Calcineurin inhibitor-free protocols** 

**10. Immunosuppression withdrawal** 

**10.1 Steroid versus steroid-free protocols** 

glycemic control, and a lower risk of bone disease.

The withdrawal of cyclosporine has been investigated in several trials. While the long-term graft survival rates were similar in patients withdrawing from cyclosporine compared to those maintained on it, the incidence of acute rejection in the withdrawal group was higher. The addition of sirolimus has been used in these withdrawal protocols. Higher rates of acute rejection were again noted in the withdrawal group.

Many other protocols that minimize exposure to calcineurin inhibitors have been studied. Promising protocols include sirolimus, MMF, and steroids or the combination of anti-CD25 antibodies, sirolimus, MMF, and steroids. These protocols have shown acceptable graft survival rates and acute rejection rates; however, these studies were small in size and further research is warranted[34]. In short, multiple regimens have been shown to be effective.

### **10.3 Pregnancy**

Current data suggest that protocols involving cyclosporine, azathioprine, and steroids are associated with low rates of birth defects. However, patients are treated with high-risk pregnancy strategies. However, children born to parents with previous transplants are often small for their gestational age. Preliminary data suggest the safety of tacrolimus. MMF animal data and some early human studies show adverse effects on fetal development. Presently, few data exist regarding sirolimus and pregnancy.

#### **10.4 Length of treatment**

Episodes of acute cellular rejection have occurred after the cessation of medication even 20 years after transplantation. For patients with stable graft function, individual components of the treatment regimen may be gradually diminished or completely discontinued; however, in most patients, some degree of immunosuppression must be continued. Some patients with severe resistant infections or malignancy related to immunosuppressants require the discontinuation of these medicines.
