Table 3.

Prophylaxis and/or treatment of GvHD

Standard pharmacologic drugs	Function	Advantages and/or disadvantages
Calcineurin inhibitors (CNIs): cyclosporine A (CsA), tacrolimus (FK506) [18]	Calcineurin is an activator of nuclear factor of activated cell (NFATc) that catalyzes some intracellular processes associated with the activation of T cells. CNIs inhibit calcineurin, which results reduced production of IL-2, prevention of T-cell activation, and differentiation [19].	In pediatric patients, the use of CNI alone prevents the severity of GvHD [20]. In general, CNIs produce nephrotoxicity causing late renal allograft loss. Calcineurin induces the release of endothelin-1 a potent vasoconstrictor
Methotrexate (MTX)	MTX is an anti-metabolite and an analog of aminopterin, the folic acid antagonist. At low doses, methotrexate attenuates the activation of T cells [21].	High doses of MTX are associated with toxicity of kidneys, gastrointestinal (GI), mucosa, and liver [22]. Hematopoiesis delays [18] engraftment and increases infection risk [20]. MTX in combination with CsA has improved the prophylaxis of GvHD.
Mycophenolate mofetil (MMF)	An anti-metabolite and prodrug of mycophenolic acid, which selectivity inhibits inosine monophosphate dehydrogenase in T cells. Combination of MMF with any calcineurin inhibitors has shown synergistic activity in the prophylaxis of GvHD [23].	The use of MMF is exclusive after non-myeloablative and cord transplants [24].
Sirolimus (SIR)	SIR binds to the intracellular protein FKBP12 inhibiting the mammalian target of rapamycin (mTOR) pathway and blocking IL-2-mediated signaling. This leads to cell cycle arrest in naïve T cells. Furthermore, SIR has permissive effect on the thymic generation of regulatory T cells allowing the expansion of them [25].	Because SIR has anti-neoplastic and antiviral properties, inhibits maturation of dendritic cells (DCs), and carries low toxicities, it is an attractive immunosuppressant agent for GvHD prophylaxis. However, SIR alone, or in combination with CNIs, is very toxic after intensive conditioning reviewed by [26].
Standard and emerging approaches to prevent or treat GvHD
Targeting allo-reactive T cells	Function	Advantages and/or disadvantages
Anti-thymocyte globulin (ATG) and alemtuzumab	Both ATG and alemtuzumab are anti-lymphocytic antibodies that suppress the reaction of host T cells enabling engraftment. In addition, both contribute to eliminate donor T cells [27].	Reduces the risk of GvHD, but attenuates the benefits GvT effects. Moreover, the recovery of lymphocytes post-transplant is hindered by these Abs, resulting in a higher risk of opportunistic infections [27].
Inhibition of protein kinase C isoforms θ and α (PKCθ and PKCα, respectively.)	- Inhibition of the activation of T cells. - Deletion of PKCθ partially blocks TCR signals and ameliorates GvHD. PKCα provides activation of IL-2 feedback. Cooperation of PKCθ with PKCα is required for T cell signaling and function.	In murine models of allo-HSCT, the inhibition of PKCθ and PKCα impaired donor T cell proliferation, migration, and chemokine/cytokine production. Also, the pharmacologic inhibition of PKCα/θ with R524 spared the T cell cytoyoxic function and the GvT effects [28].
Visilizumab (Abbottt), a monoclonal antibody against CD3.	Visilizumab a humanized monoclonal anti-CD3 Ab has a T cell receptor partial agonist ligand function induces selective apoptosis of activated T cells [29].	Safety and biological activity has been reported in clinical studies of glucocorticoid-resistant GvHD treatment, reviewed by [29]. Although the use of anti-CD3 Abs halts active autoimmunity in murine models, these Abs are less effective in preventing GvHD [29].
Bortezomib (BOR)	BOR is a selective proteasome inhibitor [30]. BOR prevents the activation of NF-κB, which is highly expressed in activated T cells. BOR targets and induces apoptosis of activated T cells and reduces the levels of IFN-γ and IL-2, [31]	Adverse effects include risk of complications, secondary infections, delay of the immune system reconstitution, graft rejection, and cancer relapse.
Statins	Statins have immunomodulatory effects, including the inhibition of antigen-presenting cells [32]. The use of Lovastatin, for example, inhibits the secretion IL-2, IL-4, and IFN-γ from primary human activated T cells [33]. Lovastatin also impairs the proliferation of donor T cells post-transplant and thus, the severity of GvHD [34].	One limitation is that the statin-associated GvHD protection was restricted to recipients co-treated with cyclosporine post-allograft engraftment [35]. On the other hand, in recipients with CSA-based post-graft immunosuppression, the use of statin at the time of allo-HSCT was associated with a decrease of cGvHD risk, but with increased risk of cancer relapse [36].