One of the nice things about OPIG, is that you can talk about something which is outside of your wheelhouse without feeling that the specialists in the group are going to eat your lunch. Last week, I gave an overview of the Hubbell group‘s Nature paper Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses. I am not an immunologist by any stretch of the imagination, but sometimes you come across a piece of really interesting science and just want to say to people: Have you seen this, look at this, it’s really clever!
When most people think of the immune system, they often think of the adaptive system, able to train itself to combat a the wide selection of hostile things your body may encounter. A key part of this is the T-cell, produced in the bones, but trained and licensed to kill in the thymus. The thymus is the T-cell thunderdome, 100 cells enter, two cell leave.
When a T-cell enters the thymus, its only hope of surviving is to prove that it is useful to the immune system and won’t cause collateral damage to the host. By this, it must be able to bind to MHCs, bind to foreign peptides and has no interest in binding to things that the body naturally produces (such as the mylean sheath around nerves or otherwise healthy tissue).
That being said however, there are reasons why T-Cells might slip through the net and recognise parts of the self, rather than foreign invaders. For more detail there is a nice paper here. But a precis is that the self-peptide may be presented at low abundance in the thymus but appear in high levels in particular peripheral tissues. It may bind to MHC in an unusual register which isn’t present in the thymus but turns up elsewhere. Or, the self-peptide may be post translationally modified in a tissue specific fashion or by the presence of other ligands or metal ions.
These self-recognising T-Cells can cause terrible problems, including auto-immune diseases from Crohn’s disease to Multiple Sclerosis, along with 70+ known others. Current methods of stopping these T-Cell loose cannons generally involve the wholesale blocking of various parts of the immune system. For example, you could use steroids to stop cytokine production. Cyclosporine to ensure T cells cannot make cytokines or proliferate. Hydroxychloroquine reduces signalling in the immune system and Prednisone depletes T-cells, B-cells and eosinophils. For an extensive view of the various methods currently in use, please take a gander at this. As these methods are blocking the immune response, they increase susceptibility to infection and cancer and don’t actually fix the problem, they just reduce the effects.
The goal of the paper was to remove the immune system memory of one molecule, with no off-target effects, using existing tolerogenic mechanisms.
The liver is unique organ in that it has two blood supplies. Blood from the intestines flows to the heart via the liver, taking with it fragments of all sorts of things. E.g., symbiotic gut microbes that don’t need attacked by the immune system. As such, the liver is essential for establishing immune tolerance. Within the liver, both Kupffer cells and liver sinusoidal endothelial cells (LSEC) are antigen presenting cells (APCs) and take antigens from the blood and cross-present them to CD4+ T-Cells together with co-stimulatory molecules. “Whereas canonical T cell activation involves the simultaneous recognition of a peptide-MHC complex by the TCR and the engagement of costimulatory molecules on the T cell, the engagement of PD-L1 on LSECs with its receptor, PD-1, on the T cell results in attenuated or alternative T cell activation and in tolerance.”
When activated in a tolerogenic manner, these T-Cells do not develop into their usual cytotoxic form, but instead develop a phenotype which causes apoptosis, anergy, colonal deletion, senescence or exhaustion. In addition to naïve T-Cells, memory T-Cells which encounter a hepatic APCs can also be forced into a different pathway which induces tolerance or deletion.
Presenting ovalbumin to OT-II mice will prompt an immune reaction as these transgenic mice express the mouse TCR which pairs with the CD4 coreceptor and is specific for chicken ovalbumin. This results in CD4+ T-Cells that primarily recognize ovalbumin. The Hubbell group took n-acetylgalactosamine (pgal) and synthetically bound an antigen to it (Ovalbumin). Doing so enhances extracellular antigen uptake by mimicking the glycome of apoptotic debris and will be rapidly taken up by hepatic APCs.
Under homeostatic conditions, liver APCs express low-to-undetectable levels of T-cell costimulatory molecules and thus present antigen in the absence of proper T-cell stimulation, resulting in abortive activation, exhaustion and suppression of effector T-cell function. “If a naïve T cell engages antigen in the absence of costimulatory molecules, such as on a nonprofessional antigen-presenting cell, inactivation occurs by either ‘clonal deletion’ or an inactive state known as ‘anergy.’ Thus, these two signals are a necessity for the activation of naïve T cells, but alone are insufficient to support strong T-cell clonal expansion, development of effector function, or establishment of a responsive memory pool.”
“KCs and LSECs express the co-inhibitory receptor programmed death-ligand 1 (PD-L1) and thus inhibit the effector function on T cells expressing programmed cell death protein 1 (PD-1) in the absence of antigen presentation.” These synthetically glycosylated antigens also expanded functional regulatory T cells, which are necessary for the durable suppression of antigen-specific immune responses.
The mice were exposed to OVA and an immune response took place, however when exposed to OVA in combination with p-GAL, the immune response for this specific antigen was successfully quiesced. The group expanded the experiment by taking myelin proteins and binding them to p-GAL and were successfully able to treat a multiple-sclerosis type disease in mice.
“The researchers note that an initial Phase I safety trial of the inverse vaccine approach has already been conducted in people with celiac disease and further safety trials are currently being conducted in people with MS. These trials are being conducted by the pharmaceutical company Anokion SA, which was co-founded by Hubbell.”
