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Jagpal et al. Vessel Plus 2018;2:24 I http://dx.doi.org/10.20517/2574-1209.2018.27 Page 3 of 14

Figure 1. Four drug groups that make up the foundation of maintenance immunosuppression in heart transplantation

Despite the combination drug regimen targeting different stages of the immune response, illustrated in
Figure 1, patients are still at risk of rejection. From 2010, 24% of heart transplant recipients have experienced
[12]
rejection . This suggests there is room for more pharmacological discovery in this area.

Immunosuppression regimens in transplantation
Immunosuppression aims to dampen the immune response in order to sufficiently permit engraftment of
the transplant, while simultaneously being suitably specific such that other protective immune responses
remain intact. This requires a complementary combination of medication that optimise immunosuppression
while decreasing toxicity. To create this balance in regimen, drugs are provided at different doses and time-
points so their effects are maximised.

Immunosuppressive treatment consists of induction and maintenance regimens. Induction therapy is
intense and occurs before, during and after transplantation in aim to markedly reduce rejection in early
postoperative period. Rabbit derived lympholytic agent, anti-thymocyte globulin (rATG) is a standard
induction drug given postoperatively. Immediate postoperative rATG therapy allows CNIs to be introduced
later. CNIs are nephrotoxic, so this action avoids exacerbation of renal dysfunction. Batches of rATG vary in
[13]
potency, thus in order to assess the effectiveness, patients T cells should be monitored with flow cytometry .

Maintenance therapy consists of a combination of drugs including: an antiproliferative, a calcineurin
inhibitor (CNI) and steroids. Although maintenance regimens are continually evolving, corticosteroids have
remained at the core since the first heart transplantation. However, due to their significant side effects, the
[14]
duration and dosage of corticosteroids has decreased with time . To combat this issue, combination therapy
has moved towards targeting steps in T-cell activation, permitting lower doses for each individual drug.

Antiproliferative agents, Mycophenolate Mofetil (MMF) and Azathioprine, operate alongside other drugs
to target the proliferation of T- and B-cells, resulting in diminished cytotoxic T-cell response [15,16] . MMF
is recommended over due to its decreased incidence of rejection and CAV [17,18] . mTor inhibitors, such as
Sirolimus, also target T-cell proliferation and are an effective alternative for CNI in patients with CNI