Follicular helper T cells and humoral response in organ transplantation.

Antibody mediated rejection has been recognized as an important contributor to long-term graft loss in most solid organ transplants. Current immunosuppressive regimes are not capable of preventing anti-HLA antibody formation and eventual damage to the graft, and there is a need to develop drugs directed against novel targets to avoid graft allorecognition. In this review we introduce follicular helper T cells (Tfh), a subtype of lymphocyte specialized in helping B cells to differentiate into plasmablasts and produce class-switched antibodies. We focus on the role of Tfh in solid organ transplantation, what is known about Tfh and the production of alloantibodies, how current immunosuppressive therapies affect Tfh and what new molecules could be used to target Tfh in transplantation, with the goal of improving graft survival.

Innate Lymphoid Cells Groups 1 and 3 in the Epithelial Compartment of Functional Human Intestinal Allografts.

We examined intraepithelial lymphocytes (IELs) in 213 ileal biopsies from 16 bowel grafts and compared them with 32 biopsies from native intestines. During the first year posttransplantation, grafts exhibited low levels of IELs (percentage of CD103(+) cells) principally due to reduced CD3(+) CD8(+) cells, while CD103(+) CD3(-) cell numbers became significantly higher. Changes in IEL subsets did not correlate with histology results, isolated intestine, or multivisceral transplants, but CD3(-) IELs were significantly higher in patients receiving corticosteroids. Compared with controls, more CD3(-) IELs of the grafts expressed CD56, NKp44, interleukin (IL)-23 receptor, retinoid-related orphan receptor gamma t (RORγt), and CCR6. No difference was observed in granzyme B, and CD3(-) CD127(+) cells were more abundant in native intestines. Ex vivo, and after in vitro activation, CD3(-) IELs in grafts produced significantly more interferon (IFN)-γ and IL-22, and a double IFNγ(+) IL-22(+) population was observed. Epithelial cell-depleted grafts IELs were cytotoxic, whereas this was not observed in controls. In conclusion, different from native intestines, a CD3(-) IEL subset predominates in grafts, showing features of natural killer cells and intraepithelial ILC1 (CD56(+) , NKp44(+) , CCR6(+) , CD127(-) , cytotoxicity, and IFNγ secretion), ILC3 (CD56(+) , NKp44(+) , IL-23R(+) , CCR6(+) , RORγt(+) , and IL-22 secretion), and intermediate ILC1-ILC3 phenotypes (IFNγ(+) IL-22(+) ). Viability of intestinal grafts may depend on the balance among proinflammatory and homeostatic roles of ILC subsets.

Human fetal neural precursor cells can up-regulate MHC class I and class II expression and elicit CD4 and CD8 T cell proliferation.

The use of allogeneic fetal neural precursor cells (NPCs) as a cell replacement therapy in neurodegenerative disorders holds great promise. However, previous studies concerning the possibility of alloimmune rejection of the transplanted cells have been inconclusive. Here, we used flow cytometry to quantify the expression of major histocompatibility complex (MHC) molecules by human NPCs, obtained from the cortex or ventral mesencephalon of fetuses with gestational ages between 7 and 11 weeks. MHC class I was undetectable on the surface of freshly isolated primary fetal tissue from either location, but increased over time in proliferating NPC cultures; after 7days in vitro, MHC class I was detectable on most cells. Following differentiation, MHC class I expression persisted on non-neuronal cells. MHC class II levels remained low at all time points but were inducible by pro-inflammatory cytokines, whereas the co-stimulatory molecules, CD80 and CD86, remained undetectable. Nonetheless, CD4+ and CD8+ T cells proliferated when peripheral blood mononuclear cells (PBMCs) were cultured with allogeneic NPCs. Weaker responses were obtained when NPCs were co-cultured with purified allogeneic responder T cells, suggesting that indirect allorecognition contributed significantly to PBMC responses. In conclusion, differentiating human NPCs are immunogenic in vitro, suggesting that they may trigger immune rejection unless transplant recipients are immunosuppressed.

The search for a curative cell therapy in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, characterised by the progressive loss of dopaminergic neurons in the substantia nigra, and typically treated by dopamine replacement. This treatment, although very effective in the early stages of the disease, is not curative and has side-effects. As such there has been a search for a more definitive treatment for this condition, which has mainly concentrated on replacing the lost neurons with neural grafts. Possible cell sources for replacement range from autologous grafts of dopamine secreting cells to allografts of fetal ventral mesencephalon and neural precursor cells derived from fetal tissue or embryonic stem cells. Some of these cells have been the subject of clinical trials, which to date have produced disparate outcomes. Therefore, whilst cell therapies remain a promising treatment for PD, there is need for further refinement of the techniques involved in this experimental procedure, before any new trials in patients are undertaken.