Approaches that prevent acute rejection of renal transplants in a rhesus monkey model were studied to determine a common mechanism of acceptance. After withdrawal of immunosuppression, all 14 monkeys retained normal allograft function for >6 mo. Of these, nine rejected their renal allograft during the study, and five maintained normal function throughout the study period. The appearance of TGF-β1+ interstitial mononuclear cells in the graft coincided with a nonrejection histology, whereas the absence/disappearance of these cells was observed with the onset of rejection. Analysis with a variety of TGF-β1-reactive Abs indicated that the tolerance-associated infiltrates expressed the large latent complex form of TGF-β1. Peripheral leukocytes from rejecting monkeys lacking TGF-β1+ allograft infiltrates responded strongly to donor Ags in delayed-type hypersensitivity trans-vivo assays. In contrast, allograft acceptors with TGF-β1+ infiltrates demonstrated a much weaker peripheral delayed-type hypersensitivity response to donor alloantigens (p < 0.01 vs rejectors), which could be restored by Abs that either neutralized active TGF-β1 or blocked its conversion from latent to active form. Anti-IL-10 Abs had no restorative effect. Accepted allografts had CD8+ and CD4+ interstitial T cell infiltrates, but only the CD4+ subset included cells costaining for TGF-β1. Our data support the hypothesis that the recruitment of CD4+ T regulatory cells to the allograft interstitium is a final common pathway for metastable renal transplant tolerance in a non-human primate model.

Induction of experimental autoimmune encephalomyelitis (EAE) has been documented in common marmosets using peptide 34-56 from human myelin/oligodendrocyte glycoprotein ) in incomplete Freund's adjuvant (IFA). Here, we report that this EAE model is associated with widespread demyelination of grey and white matter. We performed an in-depth analysis of the specificity, MHC restriction and functions of the activated T cells in the model, which likely cause EAE in an autoantibody-independent manner. T-cell lines isolated from blood and lymphoid organs of animals immunized with MOG 34-56 displayed high production of IL-17A and specific lysis of MOG 34-56 -pulsed EBV B-lymphoblastoid cells as typical hallmarks. Cytotoxicity was directed at the epitope MOG [40][41][42][43][44][45][46][47][48] presented by the non-classical MHC class Ib allele Caja-E, which is orthologue to HLA-E and is expressed in non-inflamed brain. In vivo activated T cells identified by flow cytometry in cultures with MOG 34-56, CD561 T cells also expressed CD27, but CD16, CD45RO, CD28 and CCR7 were absent. These results show that, in the MOG34-56/IFA marmoset EAE model, a Caja-E-restricted population of autoreactive cytotoxic T cells plays a key role in the process of demyelination in the grey and white matter.Key words: Common marmoset . Cytotoxicity . HLA-E . Oligodendrocytes . Natural killer-cytotoxic T lymphocyte (NK-CTL)Supporting Information available online IntroductionMultiple sclerosis (MS) is a chronic inflammatory disease of the human central nervous system (CNS) of unknown aetiology. The pathological hallmark of MS is the lesion. Lesions are regions of usually focal demyelination of variable size localized in the grey and/or white matter of the brain and spinal cord, formed by a combined cellular and humoral autoimmune attack. CNS-targeting autoimmune reactions are thought to be induced as a response to infection (response-to-infection paradigm) [1], although the pathogen(s) that elicit this pathogenic process in MS has not been identified. We have proposed a responseto-damage paradigm for MS, based on the work in a unique nonhuman primate model of MS, experimental autoimmune encephalomyelitis (EAE) in common marmosets (Callithrix jacchus), [2]. The new concept postulates that autoimmunity in MS patients is caused by a genetically predisposed hyper-response to myelin antigens released from damaged white matter due to an unknown antecedent event. We showed that the most important anti-myelin reactivity for the induction of neurological deficit is mediated by antigen-experienced T-cells specific for peptides 34-56 of myelin/oligodendrocyte glycoprotein ) [3].Subsequently it was demonstrated that these cells could be activated in vivo by immunization of marmosets with MOG in incomplete Freund's adjuvant (IFA) [4]. A peptide in IFA emulsion is a more common formulation for the in vivo activation of antigen-experienced T-cells than for autoreactive T-cells as bacterial ligands of innate antigen receptors are usually required. It is no...

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Costimulation blockade as a single immunosuppressive treatment modality is not sufficient to prevent graft rejection. Here, we report an induction therapy using antagonistic antibodies against CD40 and CD86, given twice weekly from day -1 until day 56, followed by a delayed 12-week course of low-dose cyclosporine A (CsA) treatment in the rhesus monkey kidney-allograft model. Low-dose CsA treatment was initiated on day 42 and tapered until total cessation of all treatment on day 126. Treatment with anti-CD40/86 alone resulted in graft survival of 61, 71, 75, 78, and 116 days. Costimulation blockade followed by CsA resulted in more than 3-year drug-free survival in two of four animals. None of the animals developed donor-specific alloantibodies. Transforming growth factor-beta producing cells are present in early as well as in late kidney-graft biopsies and could play a role in the observed long-term drug-free graft survival.

SARS-CoV-2 may cause acute respiratory disease, but the infection can also initiate neurological symptoms. Here we show that SARS-CoV-2 infection causes brain inflammation in the macaque model. An increased metabolic activity in the pituitary gland of two macaques was observed by longitudinal positron emission tomography-computed tomography (PET-CT). Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain, and viral RNA was detected in brain tissues from one animal. We observed Lewy bodies in brains of all rhesus macaques. These data emphasize the virus' capability to induce neuropathology in this nonhuman primate model for SARS-CoV-2 infection. As in humans Lewy body formation is an indication for the development of Parkinson's disease, this data represents a warning for potential long-term neurological effects after SARS-CoV-2 infection.

Neurofeedback may enhance compensatory brain mechanisms. EEG‐based sensorimotor rhythm neurofeedback training was suggested to be beneficial in Parkinson's disease. In a placebo‐controlled study in parkinsonian nonhuman primates we here show that sensorimotor rhythm neurofeedback training reduces MPTP‐induced parkinsonian symptoms and both ON and OFF scores during classical L‐DOPA treatment. Our findings encourage further development of sensorimotor rhythm neurofeedback training as adjunct therapy for Parkinson's disease which might help reduce L‐DOPA‐induced side effects.

SARS-CoV-2 causes acute respiratory disease, but many patients also experience neurological complications. Neuropathological changes with pronounced neuroinflammation have been described in individuals after lethal COVID-19, as well as in the CSF of hospitalized patients with neurological complications. To assess whether neuropathological changes can occur after a SARS-CoV-2 infection, leading to mild-to-moderate disease, we investigated the brains of four rhesus and four cynomolgus macaques after pulmonary disease and without overt clinical symptoms. Postmortem analysis demonstrated the infiltration of T-cells and activated microglia in the parenchyma of all infected animals, even in the absence of viral antigen or RNA. Moreover, intracellular α-synuclein aggregates were found in the brains of both macaque species. The heterogeneity of these manifestations in the brains indicates the virus’ neuropathological potential and should be considered a warning for long-term health risks, following SARS-CoV-2 infection.

The identification of FOXP3 expressing cells in recipients of an allograft, in particular inside the graft itself, may help to define criteria for immunosuppressive drug withdrawal. We therefore examined expression patterns of several regulatory T-cell (Treg) markers in kidney biopsies and kidney tissues taken at the time of graft rejection from monkeys treated with a CD40, a CD86, CsA, a combination of these or after drug withdrawal. We conclude that the presence of intragraft FOXP3+ cells is not confined to tolerated grafts, but should be considered as part of the normal immune response during rejection.