Present state of immunosuppressive therapy in liver transplant recipients

Abstract

Key Points 1. Our increasing understanding of the signaling pathways and cellular interactions in transplant immunobiology has facilitated targeted strategies using novel immunosuppressive agents. 2. The pattern of immunosuppressive drug use in the United States continues to change, and the changes include the use of antibody induction therapy and the agents used in maintenance therapy. 3. The driving forces behind the development of new immunosuppressive regimens are the long-term complications of current immunosuppressive regimens (particularly renal dysfunction and metabolic disturbances). Liver Transpl 17:S1-S9, 2011. V C 2011 AASLD.Received July 27, 2011; accepted August 9, 2011.Recent advances in molecular and cellular immunology have further unraveled the interactions between antigen-presenting cells (APCs), T cells, and B cells. These advances include the elucidation of pathways involved in T cell activation and apoptosis, the identification of novel regulatory cells (including T regulatory cells and suppressive APCs), and a greater appreciation of the complex interactions between innate and adaptive immunity. Furthermore, the elucidation of the triggers of B cell activation and antibody synthesis has allowed the development of B cell-specific immunosuppression, although the impact of donor-specific antibodies and B cells on liver transplantation (LT) is still being assessed. Nevertheless, the focus of immunosuppressive drug development has continued to be the T cell. Thus, we briefly review our current understanding of T cell activation and proliferation as well as the mechanisms of action of immunosuppressive agents.

Current Status of Immunosuppression in Liver Transplantation

“…21 Thus administration of MPA results in blockade of lymphocyte proliferation. 12 Main advantage of MPA is lack of nephrotoxicity, so it can be combined with CNI, thus permitting lower doses of CNIs. 22,23 When given alone (without CNIs), use of MPA resulted in higher rates of rejection compared to the CNIs.…”

“…This activation pathway is blocked by mTOR inhibitors (target for Sirolimus and Everolimus). 11,12 Lymphocyte proliferation requires nuc leotide synthesis. 13 Antimetabolites (Azathioprine and Mycophenolate) block nucleotide synthesis and thus work as immunosuppressants.…”

“…The most commonly used combination is to use Calcineurin inhibitor (CNI), Mycophenolate and steroids following transplantation. 12 The standard immunosuppression protocol at author's center consists of triple immunosuppression including Calcineurin inhibitors (Tacrolimus mainly), Mycophenolate and short-term steroids (tapered over three months except in hepatitis C and auto-immune hepatitis patients).…”

Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence

“…Emphasizing that over IS is detrimental to the liver transplant recipient on a number of levels (29,44,45). Additionally, there is some evidence that early acute cellular rejection after liver transplantation may improve longterm survival (29,45) as it has been suggested that complete suppression of acute cellular rejection may prevent operational tolerance from developing (45,46). Operational tolerance is where stable normal graft function is achieved without the need for IS (47).…”

Untitled

“…[5][6][7][8] It is also known that alloreactivity decreases with time after transplantation and perhaps immunosuppression can be minimized in long-term transplant recipients. 9,10 Given the significant morbidity and mortality directly attributed to immunosuppression burden, the propensity of the liver allograft to develop tolerance, and its relative resistance to acute rejection, immunosuppression minimization, especially in long-term transplant recipients, has been proposed as an ideal approach to improve long-term graft outcomes. 11,12 However, there is a clear lack of evidence and evidence-based guidelines to guide immunosuppression minimization and management in liver transplant recipients.…”