**Author details**

calcineurin-inhibitors minimization (review in [66]). Careful patient selection and close monitoring of graft function are mandatory steps for a successful conduct of a drug minimi‐

At present we still lack reliable methods to identify transplant recipients who can be weaned of immunosuppression, although a number of candidate assays have been proposed to identify operationally tolerant patients. Among them, transcriptional profiling with either microarray or real-time PCR is currently a promising approach [67]. Peripheral and intra-graft expression markers of immune activation are used as tools to guide patient selection and monitor the progress of drug minimization trials [68]. In renal transplantation, non-invasive urine bio‐ markers have been described by measuring mRNA of inflammatory cytokines [69]. In addition, studies on urine proteomics allowed to identify different causes of graft dysfunction [70]. These non-invasive tools with or without protocol allograft biopsy offer the opportunity to monitor

In recent years, advances in immunosuppression that target specific pathways of the alloim‐ mune response have been developed (review in [71]). In particular, new medications targeting the processes related to ischemia-reperfusion injury are currently under evaluation [72]. The ischemic insult to the allograft associated with the procurement and implantation processes contributes to trigger the immune activation of the recipient via the release of immunologically active substances known as damage-associated molecular patterns (DAMPs) [73]. In addition, new agents are being developed acting on the cellular and humoral mechanisms of the adaptive immune response. These include antibodies and fusion proteins interfering with Tcell-mediated activation via LFA-1/ICAM-1, CD2/LFA-3, CD40/CD154, and CD28/B7.1 and B7.2 interactions [74]. Furthermore, intracellular targets involved in T- and B-cell activation pathways are being evaluated, including protein kinase C inhibitors, Janus-associated kinase (JAK) inhibitors, and proteasome inhibitors. Several new medications demonstrate promise in inhibiting donor-directed humoral immunity by targeting B-cell-activating factor (BAFF) and complement activation pathways. Finally, other strategies are targeting the "memory"

Currently, transplant recipients are bound to lifelong immunosuppression. However, there have been reports of rare instances of "tolerance", defined as the maintenance of allograft function without immunosuppression. Although several definitions of tolerance have been proposed ("complete tolerance", "prope" tolerance, "operational" tolerance and others) and consensus is still lacking on the underlying mechanisms involved in tolerance, indeed there are patients who either intentionally or accidentally fail to reject the allograft and maintain allograft function while under minimal or no immunosuppression. As an example, in 1993 a series was reported of 11 liver transplant recipients maintaining normal liver function following the discontinuation of all immunosuppressive drugs as a consequence of either noncompliance or lymphoproliferative disorders [77]. Unfortunately, due to the heterogeneity of the human immune response, it has been so far prohibitively difficult to replicate these results on a larger number of patients and to establish tolerance in the clinical setting. The individualization of immunosuppression, identification of biomarkers of tolerance and of rejection and real-time monitoring of post-transplant immune responses may facilitate

component of the T-cell repertoire [75] or the regulatory component [76].

zation attempt in order to avoid rejection and graft loss.

846 Regenerative Medicine and Tissue Engineering

patients enrolled in trials of drug minimization.

#### Raffaele Girlanda

Georgetown University Hospital, Washington DC, USA

### **References**


allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009; 87(2):233-42.


systematic analysis in patients with protocol biopsies and indicated biopsies. Neph‐ rol Dial Transplant. 2012 Jan;27(1):435-43.)

[20] Jagadeesh D, Woda BA, Draper J, Evens AM. Post-transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations. Curr Treat Options Oncol. 2012 Mar;13(1):122-36.

allograft recipients: 24-month efficacy and safety results from the CONVERT trial.

[9] De Simone P, Nevens F, De Carlis L, Metselaar HJ, Beckebaum S, Saliba F et al., for the H2304 Study Group. Everolimus With Reduced Tacrolimus Improves Renal Function in De Novo Liver Transplant Recipients: A Randomized Controlled Trial.

[10] Woodle ES, Alloway RR, Girnita A. Proteasome inhibitor treatment of antibodymediated allograft rejection.Current Opinion in Organ Transplantation 2011; 16(4):

[11] Gerlach UA, Koch M, Müller HP, Veltzke-Schlieker W, Neuhaus P et al.,Tumor ne‐ crosis factor alpha inhibitors as immunomodulatory antirejection agents after intesti‐

[12] Lefaucheur C, Nochy D, Andrade J. Comparison of combination Plasmapheresis/ IVIG/anti-CD20 versus high-dose IVIG in the treatment of antibody-mediated rejec‐

[13] Melancon JK, Cummings LS, Rosen-Bronson S, Light J, Desai CS, Girlanda R et al., Paired kidney donor exchanges and antibody reduction therapy: novel methods to ameliorate disparate access to living donor kidney transplantation in ethnic minori‐

[14] Fishman and the AST Infectious Diseases Community of Practice Introduction: Infec‐ tion in Solid Organ Transplant Recipients American Journal of Transplantation 2009;

[15] Humar A, Snydman D, AST Infectious Diseases Community of Practice. Cytomega‐ lovirus in solid organ transplant recipients. Am J Transplant 2009; 9 (Suppl 4): S78–

[16] Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR et al., Trans‐ plantation Society International CMV Consensus Group. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation.

[17] da Cunha-Bang C, Sørensen SS, Iversen M, Sengeløv H, Hillingsø JG, Rasmussen A et al., Factors associated with the development of cytomegalovirus infection follow‐

[18] Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B et al., Val‐ ganciclovir Solid Organ Transplant Study Group. Efficacy and safety of valganciclo‐ vir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ

[19] Erdbruegger U, Scheffner I, Mengel M, Schwarz A, Verhagen W, Haller H et al., Im‐ pact of CMV infection on acute rejection and long-term renal allograft function: a

ing solid organ transplantation. Scand J Infect Dis. 2011 May;43(5):360-5.

transplant recipients. Am J Transplant. 2004 Apr;4(4):611-20.

Transplantation 2009; 87(2):233-42.

848 Regenerative Medicine and Tissue Engineering

434-438.

9 (Suppl 4): S3–S6

S86.

Am J Transplant. 2012 Aug 6. Epub ahead of print

tion. Am J Transplant 2009; 9:1099–1107.

ties. J Am Coll Surg. 2011 Apr;212(4):740-5.

Transplantation. 2010 15;89(7):779-95.

nal transplantation. Am J Transplant. 2011 May;11(5):1041-50.


[45] Ojo AO, Held PJ, Port FK. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003; 349: 931-8

[31] Aguilar-Guisado M, Givaldá J, Ussetti P. Pneumonia after lung transplantation in the Resitra cohort: a multicenter prospective study. Am J Transplant 7:1989, 2007.

[32] Newell KA, Millis JM, Arnow PM. Incidence and outcome of infection by vancomy‐ cin-resistant Enterococcus following orthotopic liver transplantation. Transplanta‐

[33] Husain S, Chan KM, Palmer SM. Bacteremia in lung transplant recipients in the cur‐

[34] Neofytos D, Fishman JA, Horn D, Anaissie E, Chang CH, Olyaei A et al., Epidemiolo‐ gy and outcome of invasive fungal infections in solid organ transplant recipients.

[35] Singh N. Fungal infections in the recipients of solid organ transplantation. Infect Dis

[36] Gavalda J, Len O, San Juan R, Aguado JM, Fortun J, Lumbreras C et al., RESITRA (Spanish Network for Research on Infection in Transplantation). Risk factors for in‐ vasive aspergillosis in solid-organ transplant recipients: a case-control study. Clin In‐

[37] George MJ, Snydman DR, Werner BG. The independent role of CMV as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Am J Med

[38] Wimmer CD, Rentxch M, Crispin A. The janus face of immunosuppression - de novo malignancy after renal transplantation; the experience of the Transplantation Center

[39] Excerpts from the United States Renal Data System 2008 annual data report. Trans‐

[40] Euvrard S, Kanitakis J, Pouteil-Noble C, Claudy A, Touraine JL. Skin cancers in or‐

[41] Leblanc KG Jr, Hughes MP, Sheehan DJ. The role of sirolimus in the prevention of cutaneous squamous cell carcinoma in organ transplant recipients. Dermatol Surg.

[42] Blaes AH, Morrison VA. Post-transplant lymphoproliferative disorders following

[43] Torbenson M Emerging causes of morbidity and mortality in organ transplant pa‐

[44] Chandok N, Watt KD The burden of de novo malignancy in the liver transplant re‐ cipient. Liver Transpl. 2012 Aug 6. doi: 10.1002/lt.23531. [Epub ahead of print]

solid-organ transplantation.Expert Rev Hematol. 2010 Feb;3(1):35-44.

tion. 1998;65:439.

850 Regenerative Medicine and Tissue Engineering

rent era. Am J Transplant. 2006;6:3000.

Transpl Infect Dis. 2010 Jun;12(3):220-9.

Clin North Am 2003; 17 (1):113-134).

Munich. Kidney Int 2007; 71; 1271-8.

plantation. Am J Kidney Dis 2009; 53 Suppl. l:S228-38

tients. Curr Opin Organ Transplant 2006; 11:304–310.

gan transplant recipients. Ann Transplant. 1997;2(4):28-32.

fect Dis. 2005 Jul 1;41(1):52-9.

1997;103:106–13.

2011 Jun;37(6):744-9.


[72] Charpentier B, Beaudreuil S, Francois H, Jacquet A, Durrbach A. Use of new nonnephrotoxic immunosuppressive drugs in kidney transplantation, especially after is‐ chemia-reperfusion injury. Bull Acad Natl Med. 2011 Apr-May;195(4-5):899-912.

[59] Cosio FG, Pesavento TE, Osei K, Henry ML, Ferguson RM. Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent

[60] Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients re‐ ceiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Trans‐

[61] Pirsh JD, Miller J, Dierhoi MH. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Trans‐

[62] Porrini E, Delgado P, Bigo C. Impact of metabolic syndrome on graft function and survival after cadaveric renal transplantation. Am J Kidney Dis2006; 48:134–142. [63] Wilkinson A, Davidson J, Dotta F, Home PD, Keown P, Kiberd B,et al., Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin

[64] Mareen R, del Castillo D, Capdevila L.Achieving chronic kidney disease treatment targets in renal transplant recipients: results from a cross-sectional study in Spain,

[65] Webster AC, Lee VWS, Chapman JR. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a sys‐ tematic review and meta-analysis of randomized trials. Transplantation 2006; 81:

[66] Vincenti F: Immunosuppression Minimization: Current and Future Trends in Trans‐

[67] Castellaneta A, Thomson AW, Nayyar N. Monitoring the operationally tolerant liver

[68] Sawitzki B, Bushell A, Steger U. Identification of gene markers for the prediction of allograft rejection or permanent acceptance. Am J Transplant 2007; 7:1091–1102. [69] Li B, Hartono C, Ding R. Noninvasive diagnosis of renal-allograft rejection by meas‐ urement of messenger RNA for perforin and granzyme B in urine. N Engl J Med

[70] Quintana LF, Sole-Gonzalez A, Kalko SG. Urine proteomics to detect biomarkers for

[71] Lunsford KE, Barbas AS, Brennan TV. Recent advances in immunosuppressive thera‐ py for prevention of renal allograft rejection. Curr Opin Organ Transplant. 2011 Aug;

plant Immunosuppression. JASN Jul 1, 2003 14: 1940-1948.

allograft recipient. Curr Opin Organ Transplant 2010; 15:28–34.

chronic allograft dysfunction. J Am Soc Nephrol 2009; 20:428–435

years. Kidney Int. 2001;59(2):732-….

plant Study Group. Transplantation 1997; 63: 977-83.

plant. 2004;4(4):583.

852 Regenerative Medicine and Tissue Engineering

Transplant. 2005;19(3):291.

1234-48.

2001; 344:947–954.

16(4):390-7.

Transplantation 2009; 87: 1340-6.

