**4. Tolerogenic strategies in renal transplantation**

Tolerance in renal transplantation is an exceptional finding. Approximately 100 cases of tolerance in renal transplantation have been reported to date, mainly in patients who were not compliant with their immunosuppressive regimens or in individuals who had previously received a bone marrow transplant for hematological disorders [52]. At the present time, in looking for tolerance in renal transplantation, physicians in clinical prac‐ tice have implemented protocols and surgical procedures in which tolerance was the planned objective before the transplant.

### **4.1. Strategies and protocols**

*3.2.3. Regulation or suppression*

470 Current Issues and Future Direction in Kidney Transplantation

gene has been described [43].

others in generating these populations [46].

tolerance induction in renal transplantation.

seen in some bone marrow transplant models [51].

T cells and certain NK populations [50]. CD8+

**4. Tolerogenic strategies in renal transplantation**

CD8+

A third mechanism of peripheral tolerance is regulation or suppression of immune responses to self or foreign antigens. Perhaps, the regulatory T cells (Treg cells) are the most important and well documented effectors of this mechanism to date. These cells control the type and magni‐ tude of the immune response to foreign antigen to ensure that the host remains undamaged. Treg cells are also integral to maintaining a lack of response to self-antigens or tolerance [40].

There are two subsets of Treg cells."Natural" Treg cells, are a thymus-derived population that constitute about 10% of the CD4 population. Natural Treg cells express CD4, CD25, CTLA4, and GITR on their surface [41], and express transcription factor Foxp3 intracellularly [42]. The importance of Foxp3 as the orchestrator of the molecular programs involved in mediating Treg function has been highlighted by diseases such as IPEX syndrome (immune dysfunction, polyendocrinopathy, enteropathy and X-linked inheritance), in which a mutation in the Foxp3

The other subset of Treg cells, commonly termed "adaptative" Treg cells, develops in the periphery, in a thymic-independent manner, following antigen encounter under particular circumstances, namely exposure to transforming growth factor-β (TGF-β). This leads to the expression of Foxp3; the hallmark of Treg cells [44]. Data suggesting the role of these cells in immunologic tolerance has been obtained from different studies in which patients with normal graft function reportedly possess a smaller Treg population compared with patients having chronic allograft rejection, suggesting that Treg cells may prevent damage and graft loss [45]. Other groups have shown that certain immunosuppressive protocols are more permissive than

The mechanisms by which Treg cells exert their effects are not completely understood. There have been two main mechanisms proposed. One mechanism requires cell contact between CD4+CD25+ Treg and responder cells and interaction between CTLA-4 and GITR molecules [47], while the other mechanism involves the induction of suppression or regulation by newly generated suppressor T cells in a cytokine-dependent manner through IL-10 and/or TGF β [48, 49]. Although promising, there is still too much to learn, before using this subset of cells for

In addition to Treg cells, there are other cell phenotypes with regulatory properties, such as

properties have been named "veto cells". Such cells maintain peripheral tolerance by attacking alloreactive T cells which are present in bone marrow with increased frequency, and may be responsible in part for the reduction in graft versus host disease and the induction of chimerism

Tolerance in renal transplantation is an exceptional finding. Approximately 100 cases of tolerance in renal transplantation have been reported to date, mainly in patients who

T cells with regulatory/suppressive

Protocols in which tolerance in renal transplantation was the planned objective before the transplant may be divided into three subgroups, namely molecule-based, cell-based, and total lymphoid irradiation.
