*4.1.1. Molecule-based protocols*

The molecule-based group includes all cases in which the induction of tolerance was attempted through administration of presumed tolerogenic drugs. These tolerogenic drugs include polyclonal antithymocyte globulin antibodies and anti-CD25 monoclonal antibodies. Anti-CD25 monoclonal antibodies competitively inhibit IL-2R-dependent T cell activation, while the polyclonal antithymocyte globulin antibodies are directed against lymphocyte antigens. The goal of the induction treatment was the nonspecific removal of clones of immune cells responsible for rejection before contact with foreign donor antigens occured. Once the donor antigens were in place after implantation of the new kidney, repletion of immune cells occured, favored by the homeostatic expansion triggered by leukocyte depletion. In addition, minimi‐ zation of maintenance immunosuppression was implemented to further reduce the anti donor response with just enough treatment to prevent irreversible immune damage to the graft, but not with such heavy treatment that the donor specific clonal exhaustion-deletion process was precluded [53].

### *4.1.2. Cell-based protocols*

In the cell-based group, patients received a donor-cell infusion of highly enriched CD34+ hematopoietic progenitor cells mixed with CD3+ T cells, [54] ie, patients received heavy conditioning regimens in association with the perioperative infusion of immunomodulatory cells, such as transplant-acceptance inducing cells. Afterward, maintenance immunosuppres‐ sion was given for a few months until complete withdrawal, when possible. Overall, although these trials demonstrated that the infusion of transplant-acceptance inducing cells is feasible, major concerns remain regarding the efficacy and safety of such an approach. Whether this approach confers any benefit in the establishment of minimal immunosuppression in renal transplantation patients when compared with the protocols currently in use is unclear. Lastly, the optimal dose and timing of cell infusions, along with the most appropriate concomitant immunosuppression regimen, remains to be determined [55,56].

Patients who received renal transplantation after bone marrow transplantation from the same donor are also included in this group. Bone marrow transplantation, when success‐ ful, generally results in the total replacement of the recipient's bone marrow with the do‐ nor's bone marrow hematopoietic cells, a condition referred to as full chimerism [57]. Experimental data have confirmed that the infusion of donor-derived bone marrow cells can prolong allograft survival by still incompletely understood mechanisms [58]. Howev‐ er, the translation of this model from animals to humans has remained a very challeng‐ ing task. In particular, an immunosuppression-free state has been achieved only sporadically after living-related donor renal transplantation, whereas similar findings have never been documented after deceased donor renal transplantation [57,59–63]. In some studies, the perioperative infusion of donor bone marrow seems to reduce the inci‐ dence of acute and chronic rejection, [57,60,61] and to improve graft function when in‐ fused not only systemically but also intrathymically [62,63].

vation and differentiation, and is the result of the release of anti-inflammatory cytokines [84,85]. Therefore, upon splenectomy, the activity of regulatory T cells is presumably af‐ fected, and this may simulate the mechanisms of action of some currently used immuno‐ suppressant drugs, such as basiliximab and daclizumab (chimeric monoclonal antibodies

Despite advances in understanding the cellular and molecular mechanisms of the alloimmune response, tolerance induction in renal transplantation remains an important clinical challenge. In clinical practice, prevention of graft rejections has combined tolerance mechanisms, such as suppression of activated T cells, inhibition the IL-2 pathway, decreased antibody production, and t chimerism. However, no completely satisfactory results have been achieved. The reason for these seemingly insurmountable challenges stems from the properties of the alloimmune

We thank Andrea Liliana López Flores, University of Guanajuato; for the preparation of drawings and we to thank Daniel Tafoya Arellano, University Quetzalcoatl of Irapuato; to help

, Beatriz González Yebra2

1 Hospital Regional de Alta Especialidad del Bajío and HGSZ No. 10 del Instituto Mexicano

2 Hospital Regional de Alta Especialidad del Bajío and Department of Molecular Biology,

\*Address all correspondence to: eduardoguani@yahoo.com.mx

4 Hospital Regional de Alta Especialidad del Bajío, México

del Seguro Social Delegación Guanajuato, México

, Éctor Jaime Ramirez Barba3

and

Tolerance in Renal Transplantation http://dx.doi.org/10.5772/54734 473

that selectively affect T lymphocytes) [86].

response, which are not yet completely understood.

**5. Conclusion**

**Acknowledgements**

carry out this chapter.

**Author details**

Marco Antonio Ayala-García1

University of Guanajuato, México

3 University of Guanajuato, México

Eduardo Guaní Guerra4

### *4.1.3. Total lymphoid irradiation protocols*

Total lymphoid irradiation was originally developed as a nonmyeloablative treatment for Hodgkin disease [64]. This treatment modality was first used about 40 years ago to in‐ duce prolonged renal allograft survival. However, total lymphoid irradiation has signifi‐ cant short- and long-term effects on lymphocyte subpopulations through suppression of activated T cells and the IL-2 pathway. Importantly, as the doses of radiation required for total lymphoid irradiation to be effective are high, with 10 doses of total lymphoid ir‐ radiation (80 to 120 cGy) targeted to the lymph nodes, spleen, and thymus, [54] its clini‐ cal application is limited by the toxicity that occurs with such high doses. With the advent of more effective immunosuppressive drugs and cytolytic therapy with antithy‐ mocyte globulin and monoclonal antibodies, the use of total lymphoid irradiation has de‐ clined considerably and is mainly applied, as stated earlier, as a nonmyeloablative preparative regimen of total lymphoid irradiation in combination with the infusion of do‐ nor-derived cells to induce a state of lymphohematopoietic chimerism [65-71].

#### **4.2. Surgical procedures**

Currently, Japan has a serious shortage of cadaveric organs. As a result ABO incompatible living kidney transplantation is being performed [72–76].

Between 2001 and 2004, the ABO-incompatible living kidney transplantation procedure used a 1-week pretransplant immunosuppression with tacrolimus/mycophenolate mofetil/methyl‐ prednisolon. During this period, splenectomy was performed in all cases and the short–term outcome was excellent [77]. Graft survival was 93.5% at three years and 91.3% at five years in these patients [78].

The spleen is involved in the production of B lymphocytes and IgM, so splenectomy can result in decreased antibody content and increased tolerance [79]. This effect could be considered analogous to the effect of rituximab (anti-CD20+ monoclonal antibody), [80,81] which prevents acute rejection mediated by antibodies, resulting in a tolerogenic effect. Conversely, recent studies show the important role of the spleen for the induction and maintenance of regulatory CD4+CD25+ T cells, which are important for self-tolerance [82,83]. This immune regulatory mechanism is known as non-specific suppression of acti‐ vation and differentiation, and is the result of the release of anti-inflammatory cytokines [84,85]. Therefore, upon splenectomy, the activity of regulatory T cells is presumably af‐ fected, and this may simulate the mechanisms of action of some currently used immuno‐ suppressant drugs, such as basiliximab and daclizumab (chimeric monoclonal antibodies that selectively affect T lymphocytes) [86].
