Natalizumab and the Lung


The ABN is saying natlaizumab is OK, but have they thought about the science?

ProfG has asked if there is a literature on neurotrophism from coronavirus? If there is would you inhibit surveillance. This is not unknown for this type of virus…food- for thought. But the main route of entry of COVID-19 into cells is via the ACE-2 receptor. This is very low in the CNS in humans.

source Brainseq

However, it is low in the lungs too but is found on lining of the lungs . In emergency medicine from a personal opinion, I would be less concerned with neurotrophic virus but in the longer-term, we may need to think about it as the virus causing COVID-2 is now likely to become an endemic human infection.

But another questions is how do immune cells get into the lung? If getting rid of the virus in the lung is important what does it. It looks like B cells and T cells.

To think there is something special about the brain and the gut where natalizumab is licenced, is marketing, not science. Biology will take the easy route.To suggest, as is done in EAE, that when you inject cells into the blood for EAE they have to go to the gut, the lungs and the lymphoid tissue before they get in the brain seems awfully complicated. Sure you find everything you inject in the blood in the lungs because it is a filtering system. In my mind there is no need to invent a special migration system to send white blood cells to this or that specific location around the body, you simply express vascular cell adhesion molecule and chemokines at the site of inflammation where you want the cells enter. The cells you want into site of infection, have receptors for VCAM-1 on their surface, to enter.

So what happens in the lung with regard to VCAM-1 expression in inflammation. Was this part of the thought process of the ABN? I don’t know. There is evidence in the mouse, but I don’t think mice have the same emphasis on adhesion molecules to say humans and guinea pigs. What happens in humans?

Did they find this

Ainskie et al. Characterisation of adhesion receptors mediating lymphocyte adhesion to bronchial endothelium provides evidence for a distinct lung homing pathway. Thorax.M P Ainslie, 

Background: The lung is an important tertiary lymphoid organ and many lung diseases are associated with disordered lung immunity. Unlike the gut (α4β7 binding to MAdCAM-1) and skin (CLA+ve T cells binding to E-selectin) where the adhesion receptors involved in organ specific homing of T cells have been identified, the molecular pathways controlling lymphocyte migration to the lung are unclear. Using a modified version of the Stamper-Woodruff assay we have investigated the receptors mediating adhesion of peripheral blood lymphocytes to airway endothelium.

Methods: Longitudinal frozen sections of bronchus (8 μm) obtained from lung resection specimens were incubated with T cell enriched peripheral blood mononuclear cells for 30 minutes under shaking conditions in the presence of a fluorescently labelled polyclonal anti-von Willebrand antibody to identify blood vessels. After fixation the percentage of blood vessels supporting adhesion was measured. Blocking monoclonal antibodies were used to determine the role of individual adhesion receptors in lymphocyte binding.

Results: Specific binding of lymphocytes to bronchial endothelium was observed which was significantly inhibited by antibodies against P-selectin, PSGL-1, L-selectin, LFA-1, ICAM-1 and ICAM-2 but not E-selectin, VLA-4, VCAM-1 or Mac-1. This was consistent with the pattern of endothelial expression of these receptors with strong expression of P-selectin and ICAM-1, but negligible expression of E-selectin on bronchial endothelium.

Conclusion: This study suggests an important role for PSGL-1/P-selectin in T cell migration into the bronchi and provides further evidence for a pattern of recirculation for respiratory tract homing T cells distinct from the gut and skin.

So it says VLA and VCAM1 are not important in getting cells into the lung, but these lungs were not inflammed.

Studies in EAE used inflammated vessels to identify that drugs like natalizumab would stop the migration (you get sections with inflammed vessels and you overlay them with lymphocytes and they stick=Stampfer Woodroofe assay), what happens in the inflammed lung? I don’t know but.

Pediatric AIDS-associated lymphocytic interstitial pneumonia and pulmonary arterio-occlusive disease: role of VCAM-1/VLA-4 adhesion pathway and human herpesviruses.Brodie SJ, de la Rosa C, Howe JG, Crouch J, Travis WD, Diem K. Am J Pathol. 1999 May;154(5):1453-64. Lymphocytic interstitial pneumonia (LIP) was characterized by lymphoid hyperplasia of the bronchus-associated lymphoid tissue (BALT) (lymphocyte expansion in lung associated lymph glands) and infiltration of the pulmonary interstitium (accumulation of cells in the lung) with CD8(+) T lymphocytes (Viral killing cells). In some individuals there was dense aggregates of B lymphocytes, many containing the Epstein-Barr viral (EBV) genome. Venular endothelium (Vein blood vessel cells) from the lung of children with LIP, but not uninflamed lung expressed high levels of vascular cell adhesion molecule-1 (VCAM-1) protein. In turn, inflammatory cells expressing very late activation antigen-4 (VLA-4) (Molecule blocked by natalizumab), the leukocyte ligand for VCAM-1, were the predominant perivascular infiltrate associated with vessels expressing VCAM-1. Expression of other endothelial adhesion molecules, including intracellular adhesion molecule-1 and E-selectin, was not uniformly associated with LIP. Using a tissue adhesion assay combined with immunohistochemistry for VCAM-1, we show that CD8(+) T cell clones that express VLA-4 bind preferentially to pulmonary vessels in sites of LIP: vessels that expressed high levels of VCAM-1. When tissues and cells were pretreated with antibodies to VCAM-1 or VLA-4, respectively, adhesion was inhibited by >/=80%. Thus, infiltration of alveolar septae (lung areas where oxygen goes from air to lungs to bloof) with CD8(+) T cells was highly correlative with VCAM-1/VLA-4 adhesive interactions, and focal expansion of B cells was coincidental to co-infection with EBV (memory B cells).

So we need to know from post-motem samples whether VCAM-1 is expressed in COVID-infected lungs. If CD8 T cells are good for the recovery and not the adverse conditions then natalizumab may blunt the anti-viral response.

Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro. Yen YT, Liao F, Hsiao CH, Kao CL, Chen YC, Wu-Hsieh BA.J Virol. 2006 Mar;80(6):2684-93

“Immunohisto chemistry from a SARS victim revealed neutrophil, macrophage, and CD8 T-cell infiltration in the lung autopsy” . So this is immunology 101 for infection control. pneumocytes in vitro express VCAM-1. In vitro experiments demonstrated that SARS-CoV, through a dynamic interaction with lung cells and monocytic (macrophages) cells, creates an environment conducive for immune cell migration and accumulation that eventually leads to lung injury.

So there is the unknown. Is the immune response causing injury or getting rid of the infection. Most likely doing both as the CD8 will kill the virally infected cell damaging the lining of the lung. So what is best? Also would this turn one into a super spreader. I don’t know. I guess we will find out. So again, give the MS register your experience. Remember the Chinese doctors are trying to use fingolimod in severely affected people. This removes cells from the blood so they can’t get into the lung. Natalizumab traps cells in the blood. So they do the same thing.

For your information ProfG tells me that development of natalizumab for asthma was stopped after PML appeared, but says there is was an increased risk of upper respiratory tract infections in the trials.

I know this doesn’t help but it gives you and any doctors reading this some insight.

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