Immune or inflammatory response by the host brain suppresses neuronal differentiation of transplanted ES cell–derived neural precursor cells

Abstract

Embryonic stem (ES) cells are a promising donor source for transplantation therapy, but several problems must be solved before they can be clinically useful. One of these is the host immune reaction to allogeneic grafts. In this article, we examine the effect of the host immune reaction on survival and differentiation of grafted ES cell-derived neural precursor cells (NPCs). We induced NPCs from mouse ES cells by stromal cell-derived inducing activity and then transplanted them into mouse brains with or without administering the immunosuppressant cyclosporine A (CsA). Two and 8 weeks following transplantation, the accumulation of host-derived microglia/macrophages and lymphocytes was observed around the graft. This effect was reduced by CsA treatment, although no significant difference in graft volume was observed. These data suggest that an immune response occurs in allografts of ES cell-derived NPCs. Intriguingly, however, the ratio of neurons to astrocytes in the graft was higher in immunosuppressed mice. Because inflammatory or immune cells produce various cytokines, we examined the effect of IL-1beta, IL-6, IFN-gamma, and TNF-alpha on the differentiation of NPCs in vitro. Only IL-6 promoted glial cell fate, and this effect could be reversed by the addition of an IL-6 neutralizing antibody. These results suggest that allogeneic ES cell-derived NPCs can cause an immune response by the host brain, but it is not strong enough to reject the graft. More important, activated microglia and lymphocytes can suppress neuronal differentiation of grafted NPCs in vivo by producing cytokines such as IL-6.

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

“…Thus, the expression of mismatched human leukocyte antigens by embryonic stem cell (ESC)-derived progeny might elicit an immune response, sufficient to induce a local immune response, if not frank rejection. In particular, activated microglia and lymphocytes triggered by engrafted cells can produce cytokines, such as interleukin 6, which can both suppress neuronal differentiation and promote astrocytic differentiation of engrafted neural precursor cells in vivo [52].…”

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

“…To overcome this limitation, studies have mainly centered on the improvement of intrinsic donor cell qualities. What is ignored, however, is that the host brain becomes hostile to grafted cells after transplantation due to immunogenic and inflammatory reactions induced by mechanical injury occurring during cell transplantation (3,4), which hampers appropriate differentiation, maturation, survival, and function of the grafted cells (5). Thus, in vitro success in donor NPC cultures efficiently yielding authentic midbrain-type DA (mDA) neurons with improved survival and functions does not guarantee successful therapeutic outcomes after transplantation without correcting hostile brain environments.…”

The Role of Immunosuppression in the Transplantation of Allogenic Neural Precursors Derived from Human Pluripotent Stem Cells for Parkinson’s Disease

“…Inflammation has a direct harmful effect on the graft and activates the immune system to generate an adaptative immune response responsible of the rejection of the graft. Inflammation has already been shown to be suppressed by the differenciation of embryonic cell-derived neural precursor [15].…”