Keeping up to date in the fast moving world of lymphatics

Research on #lymphatic_physiology has advanced in leaps and bounds. #Lymph_nodes are no longer passive filtering stations, rather the very walls of the nodes are controlling some immune interactions. #Lymph_vessels are not just a system of pumping units, we now know that the #endothelial_cells are actively checking what's in the lymph and initiating smooth muscle responses. #VEGF may explain why transplanting lymph vessels can improve #lymphoedema without the need to include lymph nodes in the graft.

It's an exciting time to be involved in lymphology but it's also a minefield of new information out there, and what do these new discoveries mean for our practice anyway? If you've ever met me you'll know that I encourage everyone to work on their literacy skills, and I don't mean reading and writing but rather the ability to appraise what you are reading about. In this blog I'm offering some simple steps to assessing the quality of what you are reading and I'll apply those steps to an interesting interview that I found online.

Step 1: How much can I trust the source?

I have a hierarchy in my head which follows academic guidelines, so a high quality peer reviewed journal is the ideal source for me, but this also requires a bit of academic skill to read. And not all articles are available free online and can be expensive to access.

The next best source would be a curated website. By curated I mean there is a moderator who has the qualification or expertise to determine the veracity of what is being posted. This might be something like an association newsletter, or a trusted organisation such as the WHO who publish fact sheets on lots of topics.

There are so many sources of information online, many of which look like they are reputable because they have 'medical' or something similar in their URL, but always have a good look at the website and if you think the source is dodgy then read the information with a high degree of skepticism. If it is a source which is selling something, then expect some bias in the way the text has been composed.

So how does my example article rate? The website is the Lymphatic Education & Research Network. A quick check on the 'About Us' tab and I can see that the people behind the scenes are mostly lymphology researchers with some big names that I recognise. This gives me faith that what is posted will have a high level of validity so I'm feel confident that I can keep reading and trust most of what I read.

When you find a reputable website like this have a look for a newsletter subscription. Getting updates in your inbox from a source you trust is an easy way to keep up to date.

Step 2: Who is telling the story?

In peer reviewed publications I can use the track record of the authors, how many other researchers have cited them, or the ranking of the journal to validate the speaker. In our example article I can look up the profile of the interviewee and see that he has a research position in microvascular surgery for lymphoedema, so I'm pretty sure he knows what he's talking about.

Step 3: What is not being said?

If something seems to be too good to be true, then it probably is. And we are all really good at optimising our successes and minimising our failures. I remember when liposuction, LVA and other transplant surgeries were first being reported at international lymphology conferences. So often the presenter omitted to mention the necessity for ongoing compression, until someone asked a question about it. And then the reply was usually "Oh yes, the patient has to continue to use compression".

20 years on and the surgery has come a long way - as is indicated in our article of interest. But human nature still persists and I would have liked it if the article had also included any negative side effects. In a peer reviewed paper the authors are required to list the limitations in their study and report any adverse outcomes. So I'm always suspicious when these things are not reported clearly, and alarm bells really go off when they are not mentioned at all. So I looked for any publications on this work to get a bit more information. There were no references in LE&RN article and I can't find anything about lymph vessel transfer without lymph nodes on Google Scholar, so there doesn't seem to be any way to check what is missing. If I really needed this information I could try contacting the author or posting a comment on the webpage.

So how did the article stack up?

Well 2 out of 3 aint bad! The online platform checks out and the person telling the story checks out so there is good reason to believe what is being said. Only one little cloud in the inability to assess what post-operative problems people might be experiencing or the rate of transfer failures.

The other new finding I mentioned in the introduction is a recent publication on fibroblastic reticular cells (FRCs). You can get the gist of it from the abstract and the author has kindly also supplied a lay summary (both pasted below). I think I would need more immune cell knowledge than I currently possess to understand the full text. But applying my 3 steps, 1: it is in PLOS Biology, a nice high ranking journal, 2: it is by an author that has multiple other publications on lymph nodes and FRCs so I think the speaker has cred. Since this is not a trial on actual people (they used discarded tonsils) 3: the reporting of adverse outcomes is not really relevant here.

In studies that don't measure clinical outcomes we are often left to interpret how these results might impact on our clinical practice. For me, understanding that the lymph nodes and lymph vessels themselves are so active in lymph flow and immune management, reinforces the need to address our clients holistically and treat the whole body, not just the problem.

Knoblich, K.; Cruz Migoni, S.; Siew, S.M.; Jinks, E.; Kaul, B.; Jeffery, H.C.; Baker, A.T.; Suliman, M.; Vrzalikova, K.; Mehenna, H., et al. The human lymph node microenvironment unilaterally regulates t-cell activation and differentiation. PLOS Biology 2018, 16, e2005046.

Abstract

The microenvironment of lymphoid organs can aid healthy immune function through provision of both structural and molecular support. In mice, fibroblastic reticular cells (FRCs) create an essential T-cell support structure within lymph nodes, while human FRCs are largely unstudied. Here, we show that FRCs create a regulatory checkpoint in human peripheral T-cell activation through 4 mechanisms simultaneously utilised. Human tonsil and lymph node–derived FRCs constrained the proliferation of both naïve and pre-activated T cells, skewing their differentiation away from a central memory T-cell phenotype. FRCs acted unilaterally without requiring T-cell feedback, imposing suppression via indoleamine-2,3-dioxygenase, adenosine 2A Receptor, prostaglandin E2, and transforming growth factor beta receptor (TGFβR). Each mechanistic pathway was druggable, and a cocktail of inhibitors, targeting all 4 mechanisms, entirely reversed the suppressive effect of FRCs. T cells were not permanently anergised by FRCs, and studies using chimeric antigen receptor (CAR) T cells showed that immunotherapeutic T cells retained effector functions in the presence of FRCs. Since mice were not suitable as a proof-of-concept model, we instead developed a novel human tissue–based in situ assay. Human T cells stimulated using standard methods within fresh tonsil slices did not proliferate except in the presence of inhibitors described above. Collectively, we define a 4-part molecular mechanism by which FRCs regulate the T-cell response to strongly activating events in secondary lymphoid organs while permitting activated and CAR T cells to utilise effector functions. Our results define 4 feasible strategies, used alone or in combinations, to boost primary T-cell responses to infection or cancer by pharmacologically targeting FRCs.

Author summary

The lymph node microenvironment contains an abundance of immune cells that interact with and within an intricate structural framework created by fibroblastic reticular cells. In mice, fibroblastic reticular cells are known to regulate T-cell activation, proliferation, and function, but in humans, they are poorly understood. We investigated interactions between human T cells and human fibroblastic reticular cells from tonsils and lymph nodes. When T cells were activated in the presence of human fibroblastic reticular cells, their proliferation and differentiation were reduced, without altering effector T-cell function, shown through cytokine production. We identified 4 molecular mechanisms that were responsible, concurrently used by all human fibroblast donors tested, and reversible upon addition of specific inhibitors to the cocultures. To establish the relevance of this finding outside of in vitro coculture, we showed that T-cell proliferation was increased in live human tonsil tissue slices when the fibroblastic reticular cell inhibitors were added. This work demonstrates that human fibroblastic reticular cells regulate T-cell activation and provides new information on the mechanisms used, which may be useful to design clinical strategies that improve T-cell responses.