Suppression of human alloreactive T cells by linear tetrapyrroles; relevance for transplantation

Abstract

The main limitation to successful transplantation is the antigraft response developed by the recipient immune system, and the adverse side effects of immunosuppressive agents which are associated with significant toxicity and counter indications such as infection and cancer. Furthermore, immunosuppressants do little to prevent ischemia-reperfusion injury during the transplantation procedure itself hence there is a growing need to develop novel immunosuppressive drugs specifically aimed at prolonging graft survival. Linear tetrapyrroles derived from the breakdown of mammalian heme have been shown in numerous studies to play a protective role in allograft transplantation and ischemia-reperfusion injury; however, commercial sources of these products have not been approved for use in humans. Plants and algae produce equivalent linear tetrapyrroles called bilins that serve as chromophores in light-sensing. One such marine-derived tetrapyrrole, phycocyanobilin (PCB), shows significant structural similarity to mammalian biliverdin (BV) and may prove to be a safer alternative for use in the clinic if it can exert direct effects on human immune cells. Using a mixed lymphocyte reaction, we quantified the allogeneic responses of recipient cells to donor cells and found that PCB, like BV, effectively suppressed proliferation and proinflammatory cytokine production. In addition, we found that BV and PCB can directly downregulate the proinflammatory responses of both innate dendritic cells and adaptive T cells. We therefore propose that PCB may be an effective therapeutic drug in the clinical setting of transplantation and may also have wider applications in regulating inappropriate inflammation.

Biliverdin and bilirubin sulfonate inhibit monosodium urate induced sterile inflammation in the rat

“…Additionally, a recent in vitro study reports that proinflammatory cytokine production, including GM-CSF, is downregulated by BV and phycocyanobilin (PCB; an algal linear tetrapyrrole structurally similar to BV) pre-treatment of human peripheral blood mononuclear cells (PBMC) stimulated by a mixed lymphocyte reaction. (49) These data agree with recent reports that BV and enzymes involved in bile pigment metabolism (BVR/Haem Oxygenase-1) inhibit sterile inflammatory responses. For example, BV treatment protects rats from acetaminophen-induced toxicity (50) , ameliorates cerebral ischemia reperfusion injury in rats (51) and supresses inflammatory cytokine release in ischemia reperfusion injury and insulin resistance models.…”

Naturally derived Heme-Oxygenase 1 inducers attenuate inflammatory responses in human dendritic cells and T cells: relevance for psoriasis treatment

“…We have previously reported that the HO-1 reaction product, biliverdin, reduces DC maturation marker expression and pro-inflammatory cytokine production 40 . We therefore hypothesised that biliverdin may be mediating the effect of carnosol/curcumin-induced HO-1.…”

Modulating Iron for Metabolic Support of TB Host Defense

“…In fact, HIF1α, which is expressed highly in lung biopsies from patients with pulmonary TB, is necessary for MMP-1 gene expression and secretion ( 184 ). Moreover, HIF1α, and DFX, has been shown to positively regulate transcript levels of heme oxygenase−1 (HO-1), an oxidative stress response protein that catalyzes the degradation of heme to Fe 2+ and other intermediaries ( 185 , 186 ). HO-1 expression is also markedly increased in rabbits, mice, and non-human primates during experimental Mtb Erdman and Mtb H37Rv infection and its expression gradually decreases during subsequent successful therapy ( 187 ).…”