04 Oct 2021
Issue #77: The monoclonal antibody story part 8: the inflammation equation
Our discussion of what the white blood cells (WBCs) do in a virus infection like COVID-19 has focused largely on the lymphocytes (#41), particularly the B cells and T cells (#7, #18, #21, #34) that are central to virus-specific ‘adaptive’ immunity and the lasting protection induced by infection or vaccination (#43, #44, #45). But we’ve said very little about the plethora of other WBC types (#7) that, originating from precursors in bone marrow (BM), are the major players in the ‘rapid response’ force that deploys, via the ‘super-highway’ of the blood, to exit into sites of virus invasion and tissue damage; cells like neutrophils (microphages) and the monocytes that differentiate to be macrophages (big eaters) are among the first ‘boots on the ground’ when a pathogen ‘sneaks through’.
Then, as the disease process develops, the innate response WBCs play different parts in eliminating the virus and clearing-up the debris from virus-damaged epithelium and other cell types. Additionally, the neutrophils and monocyte/macrophages can be ‘armed’ to become ‘targeted’ effectors when antibodies, principally the Y-shaped IgGs, attach via their Fc ‘foot’ (#20) with the two ‘arms’ that end in SARS-CoV-2 spike protein-specific binding sites sticking out. Such ‘IgG-focused’ neutrophils, monocyte/macrophages and ‘natural killer’ cells, function in the ‘innate immune army’ by mediating antibody-dependent cell-mediated cytotoxicity (ADCC), augmenting the ‘damaged-cell surveillance/elimination’ system of the CD8+ ‘killers’ that recognise (#33, #34) ‘altered-self’ molecules on the surface of virus infected cells. And, if a virus particle attaches to an IgG bound to the outer membrane of a tissue macrophage, the complex will be engulfed and destroyed in the intracellular acid pool of the lysosome.
The localised molecular changes on the surface of vascular endothelium (the cells lining the blood vessels) that cause circulating neutrophils and monocytes to leave the blood and invade into virus infected tissues are triggered initially by infected epithelial cells as they make molecules, like interferons, that are secreted into the surrounding interstitial fluid and lymph (#8). These bioactive proteins provide the ‘danger-signalling’ mechanism that gets immunity going. Some types of vaccines don’t do that adequately so we add various ‘adjuvants’. The purified (from product made in moth cells) SARS-CoV-2 spike protein Novovax vaccine, for example, incorporates Matrix-M, a saponin made from the bark of Quillaja Saponaria, the soap tree.
Back to COVID-19, that initial invasion of neutrophils and monocytes begins the process of inflammation, which is further augmented after six or more days when, exiting the responding lymph nodes, the immune B cells and T cells of the adaptive immune response also transit out of the blood into sites of infection and damage. This spectrum of tissue defenders in turn produces a range of cytokines and chemokines – we met TNF alpha recently (#75) – that have various effects, including vascular leakage, and the promotion of more inflammatory cell activation and localisation. These inflammatory processes augment the extent of physiological compromise, both as a consequence of the space they take up and the molecules they secrete, to the extent that trying to diminish the damage caused by inflammation becomes the primary focus of physicians trying to save COVID-19 patients in intensive care units.
One issue that will continue to drive inflammatory pathology in the late stages of COVID-19 can be that – especially in the very elderly and the otherwise immune compromised – the virus-specific adaptive immune response has failed to eliminate the virus. One consequence of virus persistence is that the innate immune response tries to compensate and becomes over-active. Very sick COVID-19 patients who have failed to make their own antibodies can, as mentioned last week (#76), be greatly helped by the intravenous infusion of a neutralising monoclonal antibody (mAb) specific for the SARS-CoV-2 spike protein. But there are also other anti-inflammatory strategies and it’s there that I’ll end, at least for the time being, this long discussion of the marvellous mAbs.
When patients are first hospitalised with COVID-19, they will likely be treated with low-doses of the ‘traditional’ (and cheap) anticoagulant, heparin, to minimise any blood clotting problem. Excess cytokine production as part of the inflammatory process is one of the factors that drives this ‘coagulopathy’. The next step if the patient’s condition does not improve, is to try to counter that by treating with the (again cheap) anti-inflammatory drug Dexamethasone.
If that doesn’t work and the antiviral drug Remdesivir is not helping, the next step may be to give an intravenous infusion of a mAb that blocks the pro-inflammatory cytokine IL-6, or the receptor for that cytokine (IL-6R). An example of the latter is Tocilizumab, which is used normally to treat patients with rheumatoid arthritis or the ‘cytokine-release syndrome’ associated with some forms of T cell cancer therapy (#75). A last resort in COVID-19 – apart from oxygen support, intubation and even ECMO (essentially a ‘heart-lung’ machine) – taking the IL-6 out of the inflammation equation can bring patients back from the brink.
But it comes at a cost. Apart from being expensive and available in short supply, saving the lives of COVID-19 patients with Tocilizumab can mean that those with rheumatoid arthritis, who benefit greatly from this treatment, must suffer. Vaccines keep most out of hospital with COVID-19. Vaccine refusal has a diversity of potential consequences for others.