IMMUNOSENESCENE - DECLINE  OF  IMMUNE SYSTEM  AS  WE  GROW OLD

MANILA, JULY 21, 2009 (STAR) STAR SCIENCE By Eduardo A. Padlan, PhD - Although immunosenescence increases our chances of getting sick and dying from disease, can we do something about it?

Let’s focus on the flu. How can we protect the elderly from the flu in spite of immunosenescence? Standard vaccination doesn’t seem to work.

Maybe, we could just devise new vaccination strategies.

There was a news release from the (US) National Institutes of Health in 2006 and one last year from the University of Rochester (citing work by their researchers) that giving massive doses (e.g., four times the usual) of standard flu vaccine to those who are 65 and over resulted in immunity levels that are considered protective. That’s an interesting result. But, the viruses that cause flu are constantly mutating, which is the reason we have to get flu shots every year. Should we give the elderly massive doses of flu vaccine every year? That may not be a good idea.

One of the consequences of immunosenescence is the diminished production of new immune cells (which are needed to cope with “new” pathogens). The depletion of immune cells results in “immune exhaustion,” so that our immune system is less able to mount a defense against new pathogens. Massive doses of new vaccines every year might hasten immune exhaustion.

We could vaccinate ourselves while we are still young and healthy and hope that the memory cells that are generated will last a lifetime. That is a distinct possibility. But that will work only for pathogens that do not change with time. It won’t work against the flu virus, for example, since it is constantly changing. Maybe, we could design a flu vaccine that would be protective even if the virus changes.

The principal targets of our immune response to flu are the hemagglutinin and neuraminidase molecules on the surface of the virus. It is these molecules that the clever virus changes constantly to evade our immune system. But there is another molecule that partly protrudes out of the virus membrane — the matrix protein, M2. M2 does not change and is highly conserved among the various virus strains and types. So, several groups are developing vaccines based on M2. Let’s hope they succeed. They may very well be developing a “universal vaccine” against flu.

Another possible universal vaccine against flu that is under development is one that is based on the cleavage site of the hemagglutinin, which is maintained even if the virus changes from year to year. (Hemagglutinin is what the virus uses to gain entry into target cells. But before the virus can gain full entry into the cell, the hemagglutinin has to be cleaved by an enzyme at a specific point and the cleavage transforms the hemagglutinin structure into one that permits entry.) Moreover, the segment immediately beyond the cleavage site is highly conserved among the various types of flu virus. The goal of this new vaccine is to cause the production of antibodies (immune molecules that bind with high affinity and specificity to foreign substances) that would bind to the cleavage site (or its immediate vicinity), thereby preventing the approach of the cleaving enzyme. There are indications that this strategy will work.

There are other sites on the hemagglutinin (and neuraminidase) that we could cause to be targeted by antibodies.

Antibodies normally go after the more reactive sites (epitopes) of an antigen (a foreign substance); those are the so-called “immunodominant epitopes.” Of course, it is in those immunodominant epitopes where the virus mostly makes its changes. By molecular engineering, we could decrease the reactivity (antigenicity) of the immunodominant epitopes and shift the antibody response to other parts of the antigen — to the parts that are more conserved. Then the virus could change all it wants, but we will still have antibodies (to its conserved parts) to fight the virus. (This strategy is described in full detail in a paper published last year by the author in the Philippine Journal of Science and in pending US and Philippine patents.)

And then there is the receptor binding site of the hemagglutinin, or the catalytic site of the neuraminidase, both highly conserved, which also could be the target of antibodies. If, again by molecular engineering, we could decrease the antigenicity of all epitopes, except the ones which include those sites, then we could produce antibodies that would prevent the hemagglutinin, or the neuraminidase, from performing its function. (This strategy is described in full detail in a manuscript that is in preparation and in a pending US patent application.)

Eventually (hopefully), we will develop universal flu vaccines that will protect us from all flu types, even if they change over time. And if we vaccinate ourselves while we are still young and healthy, we may be protected against flu for our entire lives. If we could do that for all the other pathogens that are constantly changing, we may have an answer to the inevitable immunosenescence.

But immunosenescence isn’t all that bad. Because the immune system has an impaired capacity to get rid of foreign substances, the elderly will have a lesser tendency to reject organ transplants. The elderly will also have a greater tolerance for immunotherapy, in particular the use of antibodies derived from non-human sources in the treatment of disease. Further, the chances of developing new allergies would be less among the elderly (since allergies are caused by the production of allergen-specific antibodies of the IgE-type).

I guess we can say that Nature isn’t really all that unfeeling. To some extent, she cares for us even when we are old.

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Eduardo A. Padlan is a corresponding member of the NAST and is an adjunct professor in the Marine Science Institute, College of Science, University of the Philippines Diliman. He can be reached at fileap-mail@yahoo.com.


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