Precision-Guided (MALT-Targeting) Mucosal Vaccines

          As an opening statement, dendritic cells rank in the "genius" league, when it comes to individual cells. THEY are the immune cells which must figure out which invaders are important, and which are not; and, when THEY determine that some particular (and apparently foreign, invading, non-self) particle is important, THEY are the cells which begin traveling toward a lymph node, to deliver that package to the B and T cells in a lymph node. The B and T cells inside a lymph node stay put, and can only wait for a mobile immune cell to show up with a chunk of "foreign" protein on an MHC mounting plaque, and then respond to whatever the mobile immune cell brought to them. So, it is dendritic cells, rather than T cells or B cells, that govern and control what the immune system will do, and how it will respond to foreign particles. Indeed, dendritic cells even determine and control whether the protein chunks from a foreign particle, will be mounted on MHC-1 proteins (which will trigger the creation of "killer T cells" that can engulf and destroy any particles having those peptide sequences on their surfaces), or whether the chunks of foreign protein will be mounted on MHC-2 proteins (which will trigger the creation of antibodies that will bind to those proteins).

          Therefore, it is dendritic cells, rather than B cells or T cells, which perform the absolutely essential, crucial, central role in determining what an immune system will respond to, and what it will not respond to.

          Therefore, if some new type of vaccine can get vaccine particles delivered directly to dendritic cells – and, if it can somehow "persuade" those dendritic cells, rapidly and reliably, that THESE vaccine particles are dangerous, and important, and merit a fast-as-possible launch of an antibody-forming response – that would be a remarkable accomplishment, and something worth serious attention, and careful study.

          And, that is exactly what MALT-targeting vaccines can accomplish.

          Backing up a bit, dendritic cells deserve a more comprehensive description, to help people better understand what they do, and how they do it.

          They do not have eyes, and they cannot see anything; and, they do not have noses, or “olfactory receptor neurons”, so they cannot “smell” things, in the way that animals with noses can smell things. What they use – instead of sight or smell – to find (and then travel toward) whatever they are looking for, at any given moment, is a cellular process called “chemotaxis”. That type of cellular travel uses multiple surface receptors which will be triggered and activated by "chemo-attractant" signaling molecules; and, those surface receptors are positioned at numerous spaced-apart locations, around the entire outer surface of each dendritic cell.

          “Chemotactic surface receptors” are specialized proteins which “straddle” a cell membrane, with one portion in an exposed outer location – where it can be contacted by “chemo-attractant” signaling molecules – while another portion is inside the cell, so it can send signals to the biochemical “machinery” inside the cell. In nearly all cases, a dendritic cell (or any other type of “mobile” immune cell) will move in the direction of the highest apparent concentration of “chemo-attractant” molecules, as indicated by signals the cell is getting from the chemotactic surface receptors on whichever side of the cell is getting the most signals, at any given moment.
         So, large numbers of newly-created “immature” dendritic cells use chemotaxis to help them locate, and settle into, “docking sites” on the “basal” surfaces of M cells, in MALT patches.
         Why do they do that?
         Because that is exactly where “immature” dendritic cells need to be, in order to be available, equipped, and ready to “spring into action”, when an “apparently dangerous particle” suddenly pops out of the basal membrane of an M cell, enters that “docking site”, and directly encounters the “waiting arms” of an “immature” dendritic cell.

          The word “immature”, when applied to dendritic cells, needs to be explained, lest anyone assume they are not yet full-grown, or mature enough, or strong enough for the tasks they must perform.

          None of those things are true; instead, “immature” dendritic cells are full-sized, fully-grown, and fully strong enough to “pick up arms, and march into battle”. However, they have not yet encountered a pathogen particle which is strong enough, and important enough, to change and transform their lives, forever. As an analogy, they are not like immature children who haven't yet reached puberty; instead, they are comparable to young men, aged 20-25, who are living in their parents' basements and whiling away their hours watching TV, texting, surfing the net, and playing video games, because nothing has “grabbed them” in a way that is strong enough to get them to move out, and begin living a “real” life. Accordingly, rather than calling them “immature” – which suggests negative things, including a lack of size, strength, skill, or capability  – they could more accurately be called “pre-transformed”, or “pre-committed.”

          The reference to “waiting arms of a dendritic cell” also merits a brief digression, to explain it. Despite the absolutely crucial role they play in launching antibody-forming responses, and in being in charge of telling the B and T cells exactly what antigen sequences they must respond to, dendritic cells were not even discovered, or known to exist, until 1973, when a fellow named Ralph Steinman recognized that a specific cell type that no one had paid attention to, previously, was much more active, and important, than anyone had previously realized. He won a Nobel Prize for that discovery, but not until almost 40 years later, in 2011, and he remains, to this day, the only person who has ever been awarded a Nobel Prize posthumously.

          As the discoverer, Steinman was entitled to name them, and he chose the name “dendritic”, from a Greek root that refers to tree branches, and other “branching”-type extensions that become smaller, as they get farther from their source, and which tend to extend outward, rather than having an appearance like a batch of stirred limp noodles.

          However, “dendritic cells” turned out to be an unfortunate name, for several reasons. One problem was that other types of cells (especially neurons) also contain branch-like projections that are also called “dendrites”; and, that overlap and conflict apparently blocked or prevented the emergence of a single-word name (such as dendricytes, or dendrocytes). Accordingly, the term “dendritic cells” became and remains the standard term, and whenever a physician or researcher hears that phrase, they must do a quick but distracting mental check to ask, “Are we talking about neurons, or immune cells, at this moment in time, and in this context?”
         In addition, subsequent research (after Steinman had already assigned that less-than-ideal name to them) revealed that their “dendrites” are not actually tubular, and do not resemble the branches of trees. Instead, they have substantial width and flatness, and are more similar in shape to petals on a flower (or leaves on a “succulent” plant), than to branches on a tree. The wider, flatter shape provides the projections with more surface area, which is needed for large numbers of surface receptors, and for surface-mediated activities that are carried out by the cells. However, it also is worth mentioning that any comparison to the shapes of petals on a flower, or leaves on a succulent plant, requires yet another qualification. Rather than being firm, engorged, and “reluctant to yield or bend”, they can shrink and collapse, if and when a need arises, and any liquid inside those protrusions apparently can be retracted, into the main cell body, if a need arises; and, that is yet another important trait and capability of dendritic cells, because that capacity is a crucial part of how they travel, or “migrate”, if and when a need arises. They are capable of using a type of motion called “pseudopod migration”, which is used by amoebas (and by octopuses, if they are challenged to squeeze through a small hole or gap, to get to a fish or crab). That type of travel enables dendritic cells to squeeze through the lymph-filled gaps between neighboring cells, in soft tissues.

          Returning to the main subject, large numbers of newly-created “pre-committed” dendritic cells are actively recruited (via chemo-attractant signaling molecules) to find, and settle into, docking sites on the basal surfaces of M cells in MALT patches. Those docking sites are the perfect locations for newly-formed dendritic cells to go to, so that they will be ready to respond, quickly and directly, when an M cell pulls in an apparently dangerous particle (i.e., having a “pathogen pattern” on its surface), and rapidly transports that particle (isolated inside a phagosomal bubble) through the cell. When the M cell ejects that particle into its docking site (in “naked” form again, after the phagosome holding the particle merges with the “basal” membrane of the M cell), that particle will be delivered directly to the surface of a dendritic cell, which has been patiently waiting for exactly that type of “pathogen delivery,” by the M cell which created (and which controls) that docking site.

          When a dendritic cell receives such a particle, it  will use a complex and sophisticated set of numerous surface receptors to analyze that particle, and the cell will then “commit” to either of two very different options:
         OPTION 1:    If the particle appears to be “not really important”, the dendritic cell can simply take it in, break it apart (i.e., digest it), and release its “biochemical building blocks,” so that other cells can use those building blocks for their own nutrition; and then, that “unchanged, not-yet-activated, unmoving, still-immature” dendritic cell can simply wait, without further ado or commotion, in that same docking site, for the next “pathogen delivery” from that M cell;  
         – OR –
         OPTION 2: if the particle appears to be a dangerous and important pathogen which merits a full-scale “antibody forming” response . . .  then . . . that dendritic cell will “commit” to an “activation/maturing/transforming” event, which will become a major “life-changing” event, for that “previously immature” dendritic cell.

          Accordingly, when a dendritic cell finishes analyzing a particle which has been handed to it by an M cell, the dendritic cell must choose between the two options described above. There are no other, alternate, “partial” or “halfway” options available. A dendritic cell must commit, fully and completely, to either activating, maturing, and leaving that docking site; or, it must remain in place, without making that transition. By way of analogy, when a train leaves a station, a person is either on that train, or not on that train; there are no halfway or partial options available (at least, not for people who are still alive, and have all their limbs still attached).
         Therefore, if vaccine particles can be made to APPEAR to be extremely pathogenic, dangerous, and important – by placing one or more peptide sequences on them which, in nature, are on the surfaces of the most dangerous and important types of pathogens that exist in nature  – then those peptide sequences can trick and fool dendritic cells into “believing” that those vaccine particles are indeed extremely dangerous and important. And, if that can be accomplished, then dendritic cells which receive those types of vaccine particles, as “pathogen deliveries” coming from M cells in MALT-patches, will rapidly and irrevocably commit to activation, maturing, and leaving the docking site which belongs to that M cell, to go find the germinal center of a lymph node, using the process called “antigen presentation.”

          That is exactly what an effective “MALT-targeting” sequence (as described herein) can do. A good and potent MALT-targeting sequence can (and will) cause surface-exposed M cells, in MALT patches, to actively pull in those apparently dangerous and important particles, rapidly push them through the M cell, and eject the particle (in naked form again), directly into the M cell's docking site, which will hold an immature dendritic cell. Once that has been accomplished, those same MALT-targeting sequences can (and will) cause immature dendritic cells (which are waiting for pathogen deliveries, in those docking sites) to interpret those “pathogen pattern” danger signals in ways that will rapidly drive those dendritic cells into a full and irreversible commitment, to convert into an activated/maturing dendritic cell, which will leave that docking site, and go off in search of a “germinal center” in a lymph node (i.e., a place where T and B cells wait for “antigen-presenting cells” to bring them new challenges).
         Those are exactly the types of responses, by exactly the right types of immune cells, that will trigger, launch, and drive the type of antibody-forming response that vaccines particles are designed and intended to create.

         And, it gets even better than that, for three reasons that can be summarized as:  
         (i)    The “newly activated” dendritic cell will not need to spend hours, or sometimes days, slowly using amoeba-like “pseudopod” travel to squeeze through the narrow lymph-filled gaps between cells, trying to find the inlet to a “lymphatic drainage channel”, which will then (slowly) carry that activated cell to a lymph node. Why not? Because MALT patches are already lymph nodes, which happen to be mounted on the surfaces of mucosal membranes. A newly-activated dendritic cell, when ready to leave a docking site behind an M cell, is already fully inside a lymph node.
         (ii)    The use of “MALT-targeting” peptides can completely eliminate any need for using the types of irritating, inflammatory, and toxic additives that are called adjuvants, which are necessary to make injected vaccine more effective. That topic is discussed in more detail, HERE.
         (iii)    When these types of MUCOSAL vaccines are used, they will trigger and drive the formation, not just of the standard, typical, Y-shaped “internal” (IgG) antibodies that are triggered by injected vaccines, but also, an entirely different type and class of “secreted mucosal (IgA) antibody dimers”, which have very different structures, and very different functions, than internal antibodies. That topic is discussed in more detail, HERE.