Inhibition of S-adenosyl-L-homocysteine hydrolase alleviates alloimmune response by down-regulating CD4+ T-cell activation in a mouse heart transplantation model

Background: Transmethylation reactions play an important role on lymphocyte activation and function. S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitors prevent the feedback of transmethylation reactions by S-adenosyl-L-homocysteine (SAH) accumulation, a competitive antagonist of S-adenosylmethionine (SAM)-dependent methyltransferases. However, the role of SAH in solid organ transplantation is currently unclear.

Methods: A murine model of cardiac transplantation (BALB/C to C57B/6) was established to assess allograft survival, histology, and T cell infiltration. The reversible SAHH inhibitor, DZ2002, and irreversible SAHH inhibitor, adenosine dialdehyde (AdOx), were used to assess their immunosuppressive effects in murine cardiac transplantation, compared with mice with DMSO.

Results: Both SAHH inhibitors prolonged the survival of cardiac allografts and alleviated alloimmune response. Notably, AdOx and DZ2002 both eliminated frequencies of Th1 and Th17 in CD4⁺ T cells in cardiac transplantation, and reduced the frequency of active CD4⁺ T cell (CD44⁺ CD62L^-). The irreversible SAHH inhibitor facilitated the differentiation of regulatory T cells (Tregs) and increased Bim expression. Furthermore, both SAHH inhibitors alleviated infiltration of CD4⁺ T cells in cardiac allografts.

Conclusions: The SAHH inhibitors (AdOx and DZ2002) alleviates allograft rejection in cardiac transplantation by inhibition of CD4⁺ T alloimmune response. SAHH inhibitors, especially DZ2002, is a promising complementary therapeutic agent in organ transplantation.