ESOT 2013 Report – Who needs tolerance in the age of immunosuppression minimization?

Reducing or eliminating the need for chronic immunosuppressive therapy by inducing tolerance in the recipient immune system would have an astounding impact on clinical practice and scientists all over the world are working tirelessly to find the ‘magic bullet’ immunotolerance protocol . From a clinical perspective, tolerance induction is still some way over the horizon; however, a series of recent studies have shown encouraging results which suggest that immune tolerance and/or minimisation of immunosuppressive therapy may become part of routine management protocols in the not too distant future.

 

Addressing the subject of tolerance, Professor Jean-Paul Soulillou summarised the recent findings from a clinician’s view. To induce immune tolerance, the conditioning therapy must be capable of overcoming both the memory cells of the naïve immune system, and thymic alloreactive T-cells arising de novo post transplantation. In 2011, a proof-of-concept study  was published in which 12 HLA-matched kidney transplant recipients received CD34+ and CD3+ T cells together with total lymphoid irradiation, anti-thymocyte globulin (ATG) and conventional immunosuppressive therapy. Eight of the 12 patients were able to discontinue their immunosuppressive therapy for up to three years without any signs of rejection [1]. More recently, 10 patients who received conditioning with cyclophosphamide, thymic irradiation, anti-CD2 monoclonal antibody, and an 8-to-14-month course of a calcineurin inhibitor (CNI) have remained well without maintenance immunosuppression for up to 10 years, and the authors concluded that transient chimerism is sufficient for inducing stable tolerance [2]. In addition, protocols involving nonmyeloablative conditioning with bioengineered stem cell transplantation have been shown to achieve durable chimerism in mismatched allograft recipients [3, 4]. In Professor Soulillou’s view, it is too early to say whether tolerance is a realistic proposition in the clinic, but the available data is encouraging and in his view, a European study should be initiated.

 

If outright tolerance may not be readily achieved, minimisation of immunosuppressive medication may be a more realistic proposition. Professor Ron Shapiro from Pittsburgh summarised the clinical experience from his own and other centres and pointed out that whilst steroid withdrawal or avoidance is successful in most cases when attempted, withdrawal or avoidance of CNI immunosuppression has proved much more of a challenge.  A protocol of induction with alemtuzumab followed by spaced weaning of CNI therapy that was tried at the Cleveland clinic showed comparable patient survival and graft function over three years with fewer complications compared with a reference protocol with no antibody induction; however, amongst the patients who were weaned from immunosuppressive therapy, the rate of acute rejection rose to 25% and the study had to be discontinued [5]. Despite this, a proportion of patients who were weaned off CNI therapy remain well 10 years on, and Professor Shapiro hypothesised that improved immunological surveillance in terms of monitoring the levels of donor-specific antibodies (DSA) may allow clinicians to better predict the outcome of the weaning procedure.

 

Greater success has been achieved by a team led by Professor Allan Kirk at Emory University, with a protocol involving alemtuzumab induction with belatacept and sirolimus immunosuppression for one month. To date, two-year patient and graft survival has been excellent, and 10 patients have been weaned off sirolimus altogether [6]. In addition, the protocol of nonmyeloablative conditioning with bioengineered stem cell transplantation described by Professor Soulillou may have a role to play for minimisation as well as tolerance induction [3]. Professor Shapiro concluded that although efforts to taper CNI-based immunosuppression to date have been largely empirical, novel protocols together with more stringent strategies for monitoring the immune system is the likely way towards success in this field.

 

References

1. Scandling, J.D., et al., Induced immune tolerance for kidney transplantation. N Engl J Med, 2011. 365(14): p. 1359-60.

2. Kawai, T., et al., HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med, 2013. 368(19): p. 1850-2.

3. Leventhal, J., et al., Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome. Transplantation, 2013. 95(1): p. 169-76.

4. Leventhal, J.R., et al., Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance. J Am Soc Nephrol, 2013. 24(9): p. 1376-85.

5. Tan, H.P., et al., Two hundred living donor kidney transplantations under alemtuzumab induction and tacrolimus monotherapy: 3-year follow-up. Am J Transplant, 2009. 9(2): p. 355-66.

6. Kirk, A.D., The cam-path forward. Am J Transplant, 2013. 13(1): p. 9-10.