Immune problems in central nervous system cell therapy

Abstract

Summary:Transplantation of cells and tissues to the mammalian brain and CNS has revived the interest in the immunological status of brain and its response to grafted tissue. The previously held view that the brain was an absolute "immunologically privileged site" allowing indefinite survival without rejection of grafts of cells has proven to be wrong. Thus, the brain should be regarded as a site where immune responses can occur, albeit in a modified form, and under certain circumstances these are as vigorous as those seen in other peripheral sites. Clinical cell transplant trials have now been performed in Parkinson's disease, Huntington's disease, demyelinating diseases, retinal disorders, stroke, epilepsy, and even deafness, and normally are designed as cell replacement strategies, although implantation of genetically modified cells for supplementation of growth factors has also been tried. In addition, some disorders of the CNS for which cell therapies are being considered have an immunological basis, such as multiple sclerosis, which further complicates the situation. Embryonic neural tissue allografted into the CNS of animals and patients with neurodegenerative conditions survives, makes and receives synapses, and ameliorates behavioral deficits. The use of aborted human tissue is logistically and ethically complicated, which has lead to the search for alternative sources of cells, including xenogeneic tissue, genetically modified cells, and stem cells, all of which can and will induce some level of immune reaction. We review some of the immunological factors involved in transplantation of cells to CNS.

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell Replacement Therapy for either Huntington’s or Parkinson’s Disease

“…Of course, immune rejection and the broader context of inflammation also enter into this equation, given the common desire to utilize transplants in the context of deteriorative diseases or trauma-related damage. While it is arguable that convincing the immune system not to overreact has been extensively studied as a factor in this context (e.g., [64]), the inflammatory response certainly has the capacity to tailor the very adaptation mechanisms we will discuss (e.g., [65]). For extensive reviews of the reciprocal interactions between neural systems and inflammatory systems relevant to plasticity see Di Filipo and colleagues [66], or Xanthos and Sandkuhler [67].…”

Neurodegeneration and cell replacement

“…The CNS was thought to exhibit this privilege because blood-brain barrier protection, antigen-presenting cell paucity and limited lymphatic drainage prevented efficient adaptive immune response activation. Because cellular grafts survive long term in the human CNS without immunosuppressant therapy (Freed et al 2001), few transplant studies have fully assessed the role of inflammation in graft survival or long-term function (for excellent reviews on mechanisms governing graft rejection see Barker & Widner (2004) and Bradley et al (2002)). However, post-mortem examinations of foetal mesencephalon-derived graft recipients (independent of the post-transplant immunosuppressant regime) reveal activated microglia and host immune cell infiltration at the host-graft interface and throughout the graft (Freed et al 2001;Olanow et al 2003), strongly suggesting that inflammation compromised graft survival and functional outcome.…”

“…Cells transplanted into parenchyma survive better than those transplanted periventricularly (Barker & Widner 2004), potentially owing to proximity to infiltrating antigen-presenting cells near periventricular zones. The probability of immune system-mediated graft rejection also increases with the degree of trauma produced by the transplant procedure.…”

“…Studies investigating the safety and efficacy of transplanted neural tissue have generated little consensus about the need for immunosuppression, and there is a dire paucity of information about immunologic interactions between host and stem cell-derived transplants (Bradley et al 2002;Barker & Widner 2004). Experience with foetal tissue in clinical trials suggests that outcome is improved with immunosuppressant therapy.…”

Human Bone Marrow Stromal Cells can Differentiate to a Retinal Pigment Epithelial Phenotype when Co-Cultured with Pig Retinal Pigment Epithelium using a Transwell System

“…By expansion in an in vitro system, adult stem cells can provide enough seed cells for cell transplantation [13,14]. Furthermore, adult stem cells are attractive candidates for cellular therapies, due to the distinct advantages of autologous availability and any ethical concerns associated with other stem cells [15]. Recently, it was shown that adipose tissue-derived mesenchymal stromal cells have the differentiation potential to become RPE-like cells [16,17].…”