**8.2. Treatment of humoral rejection**

Humoral rejection mediated by alloreactive B-cells, alloantibodies and complement are more challenging to treat. Humoral rejection is often refractory to treatment and continues to be a significant problem in transplantation due to difficulties in establishing a consensus for safe optimal treatments directed against allosensitization and alloantibody production. Humoral responses also greatly contribute to late acute graft losses and the development of chronic rejection. [62] Humoral rejection has been linked to the presence of donor specific antibody and activation of complement resulting in C4d deposits in renal tissue. Therapeutic strategies have been aimed both at removing alloantibodies as well as decreasing alloantibody produc‐ tion by impairing and/or depleting B-cells. [63, 64]

The best known treatment algorithms to treat antibody mediated rejection include combina‐ tions of plasma exchange to remove donor-specific antibody, and/or intravenous immuno‐ globulins and the anti-CD20 monoclonal antibody (rituximab) to suppress donor-specific antibody production. [65, 66] There are no randomized controlled trials powered to show efficacy or safety of potential different combinations of these different therapeutic strategies. Some side effects of plasmapheresis include hypotension, citrate induced hypocalcemia, complications with access placement, and infections due to removal of immunoglobulins. Adverse reactions of IVIG include anaphylactoid reactions, fevers, chills, flushing, myalgias, malaise, headache, nausea, vomiting, dilutional hyponatremia, pseudohyponatremia, hemol‐ ysis and neutropenia. See previous section on Rituximab for side effects.

Bortezomib continues to be a promising agent for acute humoral rejection because of its ability to target multiple pathways involved in B-cell activation and antibody production and its direct activity against CD138+ long lived plasma cells that exist in survival niches such as the bone marrow and spleen. [67] These cells, primarily responsible for producing high affinity alloantibody, are not targeted by Rituximab, the current mainstay treatment for humoral rejection. [68, 69] Initial reports on Bortezomib were in patients with AMR that were refractory to traditional anti-humoral therapies, but recent reports show that Bortezomib can be used as primary therapy for AMR. [70] In terms of its ability to decrease the levels of donor specific antibodies in sensitized patients and patients with AMR, studies have provided mixed results. [71, 72] Part of this may be secondary to differing conditioning regimens that accompany the use of Bortezomib. Another important finding reported by two studies is the differential responses of early versus late AMR after treatment with Bortezomib, with early AMR re‐ sponding much better than late. [25]

transplantation and autoimmunity. [74, 75] Whether tolerance can be generated in vivo in

Maintenance Phase 1 Humanized antibody

Belatacept is a relatively new agent used in human transplantation with the first report of its use in human renal transplantation in 2005. The focus of clinical investigative trials utilizing belatacept was to provide a new effective maintenance regimen that would allow for the avoidance of the renal and metabolic side effects of chronic CNI use. Studies such as the BENEFIT and BENEFIT-EXT trials demonstrate its efficacy as a maintenance agent in place of calcineurin inhibitors. [76] The three year follow up data of BENEFIT where belatacept was compared to cyclosporine concluded that patient and graft survival were comparable with better GFR in the belatacept arm. There was however increased incidence of acute rejection and early post transplant lymphoproliferative disease in the belatacept group (especially in EBV sero negative patients). For this reason, belatacept use is approved only for patients who are EBV seropositive. The cost and long term need for intravenous administration of the drug appear to be major obstacles for wide spread use of belatacept. Nevertheless, it still provides

Establishing optimal immunosuppressive regimens involves maintaining a delicate balance between over-immunosuppression which increases infection risk and under-immunosup‐ pression which increases risk of allograft rejection. Use of potent induction agents and main‐ tenance therapies that include CNI has led to dramatic decrease in the incidence of acute rejection episodes in the immediate post transplantation period. However, late allograft loss

Target ?/? T-cell receptor Induction Phase 2

?

**Mechanism of Clinical Indication Studies**

Maintenance Phase 2

Studies halted secondary to increased rejection rates

Overview of Immunosuppression in Renal Transplantation

http://dx.doi.org/10.5772/54865

223

against CD40 on antigen

Inhibitor of the JAK-STAT pathway.

Blocks T-cell activation

Non-depletional Inactivates T-cell

**action**

Protein kinaseC inhibitor Maintenance

Blocks T-cell activation

presenting cells **ASKP1240** 

**[77-79]**

**Tofacitinib**

\**References* 

a valuable alternative to long term CNI use.

**Table 4.** Novel Immunosuppressive Agents

Table 4 pg. 19

**10. Conclusion**

\*References [77-79]

**Sotrastaurin**

humans, however remains to be seen.

**Agent**

**TOL101**
