In general, autologous cells C whether DA or NPCs of additional mind regions C evoke no or only negligible T-cell response and so will not require any immunosuppressive therapy. progenitors have also been proven to be effective in pre-clinical animal models of PD AZD1981 in AZD1981 terms of graft survival, DA release, local innervation and reversal of behavioural deficits [16C18]. However, their security and effectiveness in individuals is definitely unfamiliar but early tests with these types of grafts are now starting [20,21]. The use of therapies of this type brings with it a number of difficulties including those linked to the controlled differentiation of the cells to authentic A9 DA neurons without cell overgrowth/tumour formation, graft survival and connectivity, practical effectiveness and finally their immunogenicity and the need for sponsor immunosuppression [22]. This review focuses on this last issue, namely their immunogenicity. The immune system and the brain Immunogenicity of a transplant is definitely defined as the ability of the cellular antigens in the grafted cells or cells to evoke an immune response in the sponsor leading to an infiltration of lymphocytes into the graft site and potential rejection. Such reactions are primarily of two types C cellular and humoral immune reactions. The cellular immune response is mainly driven by T cells which recognise foreign alloantigens presented with major histocompatibility complex (MHC) within the cell surfaces of antigen-presenting cells (APCs); co-stimulatory molecules also play a role with this connection. This alloantigen recognition by T cells can AZD1981 be through one of three types C direct, semidirect and indirect (see Figure 1). Open in a separate window Physique 1 Types of alloantigen recognition by T cells In direct allorecognition, alloantigens from the graft are presented by donor APCs to T cells of the host, whereas indirect allorecognition is usually one in which donor-derived antigens are captured by host APCs and then presented to host T cells eventually Rabbit polyclonal to AADACL2 eliciting an immune response. In semidirect recognition, cell-to-cell contact between donor and recipient APCs may transfer intact donor MHC molecules to recipient APCs, or donor APCs may release exosomes made up of MHC molecules which then fuse with the recipient APC membrane. As a result, recipient APC becomes chimeric with both donor and recipient MHC molecules, which can then stimulate both direct and indirect pathways [23,24]. The humoral immune response is usually primarily driven by B cells whereby, upon recognition of foreign antigens from the graft, they differentiate to plasma cells and produce antibodies against the antigens to drive antibody-mediated rejection. In addition, the transplant may also express epitopes to which the host has pre-formed antibodies C e.g., as is seen in porcine xenografts with host anti-Gal antibodies [25]. This B-cell response is considered a major barrier in transplantation because conventional immunosuppressants largely target T cells. Such humoral responses and the generation of antibodies can activate the complement cascade which facilitates antibody-mediated rejection which is usually hyperacute for xenogeneic tissue placed in the periphery but much slower with allografts. Complement additionally recognises apoptotic and necrotic cells and modifies antigen presentation to B AZD1981 and T cells [26]. However, allogeneic graft rejection of cell suspension transplants in the CNS is different from that seen with peripheral organ transplants. The first difference relates to the use of cell suspensions in the brain as opposed to whole organs C as the latter have a vasculature with a donor-derived endothelium which is usually highly immunogenic. Secondly, foetal neural cells (which have been the main cells used for grafting into the brains of patients with PD) have been shown to express no or only low levels of immunogenic molecules [27,28]. The third major difference relates to the bloodCbrain barrier (BBB) that is jointly maintained by endothelial tight junctions, endothelial basal lamina and astrocyte endfeet processes. This BBB makes the brain a relatively immune privileged site given it represents a physical barrier to molecules of high molecular weight and cell transmigration from the circulation into the brain. Fourthly, the CNS lacks professional APCs. Microglia, which are the resident CNS macrophages, unlike peripheral dendritic cells (DCs), have reduced capacity in presenting antigens to induce T-cell proliferation..