Immune response to stem cells and strategies to induce tolerance

Abstract

Although recent progress in cardiovascular tissue engineering has generated great expectations for the exploitation of stem cells to restore cardiac form and function, the prospects of a common mass-produced cell resource for clinically viable engineered tissues and organs remain problematic. The refinement of stem cell culture protocols to increase induction of the cardiomyocyte phenotype and the assembly of transplantable vascularized tissue are areas of intense current research, but the problem of immune rejection of heterologous cell type poses perhaps the most significant hurdle to overcome. This article focuses on the potential advantages and problems encountered with various stem cell sources for reconstruction of the damaged or failing myocardium or heart valves and also discusses the need for integrating advances in developmental and stem cell biology, immunology and tissue engineering to achieve the full potential of cardiac tissue engineering. The ultimate goal is to produce 'off-the-shelf' cells and tissues capable of inducing specific immune tolerance.

Figure 1

Routes for evading immune rejection of human ES cells.

Figure 2

MSCs induce the release of anti-inflammatory Th2 cytokines and the Th2 chemokine, I-309, a major chemoattractant for regulatory T(reg) cells, but downregulate Th1 pro-inflammatory cytokines. Supernatants were collected following 48 h co-culture of either (a) primary T cells with allogeneic peripheral blood mononuclear cells (PBMCs), two isolates of IFNγ-treated MSC (1 and 2) or IFNγ-treated allogeneic endothelial cells (ECs) or (b) primed DR11-specific T cells with allo-specific DR11 expressing PBMCs, IFNγ-treated DR11-expressing ECs, IFNγ-treated DR11-expressing MSCs or IFNγ-treated third party MHC mismatched MSCs. Cytokines detected from 48 h supernatants from T cells alone (primary and primed) and untreated or IFNγ-treated MSCs alone are also shown. Secretion of cytokines was measured using the RayBio Human Cytokine Array III system. Sections of the membrane detecting a range of Th1 and Th2 cytokines are as shown and the results are shown as signal spots.

Figure 3

MSCs constitutively express high levels of HO-1 when compared with endothelial and valve interstitial cells (IC).