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48

Pneumonia

Dr, Avery and Associates.

Work on pneumonia and the pneumococcus has continued to progress.
The treatment of pneumococcal pneumonia by means of antipneumococcal rab-
bit serum, & therapeutic agent developed in the Hospital, yields excellent
results. Despite the progress already made, much remains to be learned
concerning many aspects of the problem. The results of Dr. Goebel's work
on the production of an antiserum for pneumococci by the uso of a synthet-
4c antigen aro vory encouraging, and it ig hoped that this work will open
up a new approach to the production of certain therapoutic sora.

Preparation and use of thetic antigen in the production of
antipneumococcal sera. Yor a number of years one of the major problems
under investigation in the Hospital of The Rockefeller Institute has been
a study of pneumococcus pneumonia, one of the most fatal of the acute in-
fectious diseases in man. Methods were devised for studying the inter-
action of pneumococci and the tissue of the host, and the results were
practically applied in the diagnosis and treatment of this disease long
before the chemical nature of the substances involved were known.

In recent years the contributions of chemistry have added mich
to our understanding of the nature and specificity of these immunity re-
actions. As a result of these investigations it has been found that
pneumococci) are not all alike, but exhibit among themselves differences
in biological specificity as diverse as though they were members of wholly
unrelated species, Upon the basis of these differences pneumococci have
been classified into thirty-two sharply defined and specific types. These
researches have led to the development of curative sera, derived from the

blood of immnized animals, which have been singularly succeesful in the

 

 

 

 

 
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49

treatment of the disease in man.

That pneumococci are enveloped by a mucilaginous capsular sub-
stance which serves as & protective coating to the microorganisms per~
mitting them to grow and miltiply in the invaded host, has been known for
many years. One of the most significant results of the chemo-immnological
studies carried out in the Hospital has been the discovery that the differ-
entiation of the various specific types of pneumococci is dependent upon
chemical differences in their capsular substances. It has been revealed
that each distinct type of pneumococcus builde about itself from the me-
dium of its environment an encapsulating carbohydrate, the molecular ar-
chitecture of which is in each Anstance difforent. Just as one may build
an infinite variety of structures from the same pbuilding stones, so it is
possible for each type of pneumococcus to construct an individual and
characteristic capsular polysaccharide from the same atoms of carbon,
hydrogen, and oxygen. The chemical approach to an understanding of the
differentiation of the various pneumococcal types and their varied bio-
logical behavior resides in the comprehension of this fundamental differ-
ence in the chemical structure of the capsular carbohydrate peculiar to
each specific typo. For example, it has been found that the capsular
polysaccharide of Type III Pneumococcus is a complex sugar which in many
respects bears 4 striking relationship to cellulose, a substance univer~
sally distributed in nature, Cellulose is constituted from many molecules
of the simple sugar glucose, which are combined to one another by means
of a chemical linkage. On boiling with acid, cellulose may be broken down
to the simple sugar glucose, OF, if the hydrolysis is carried not quite
so far, to a sugar made up of two glucose molecules. This latter sugar

is called cellobiose. Now if the terminal, or twelfth carbon atom of

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50

cellobiose is oxidized to an acidic group the sugar-acid "cellobiuronic
acid" is obtained. It is this substance which constitutes the fundamental
puilding stone of the complex capsular carbohydrate of the Type III Pneumo-
coccus.

When the capsular polysaccharide of Type II! Pneumococcus is
isolated in pure form 4t ig found to be devoid of certain {mmunological
properties which it possessed in its native state in the capsule of the
parent cell. No longer is it possible to induce in rabbits immunity to
Type III pneumococcal infections by injection of the purified carbohy~
drate. But by chemical synthesis one may combine this gingle cellular
constituent of the Type III Fnoumococcus with a protein to yield an ar-
tificial substance, which when injected into rabbits is capable of in-
citing specific immunity to infection with virulent homologous organisms.

Cellobiuronic acid 4g found not only in the capsular polysaccha~

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ride of the Type III Pneumococcus, but it and other closely related sugar '

acids are present in the specific carbohydrates of other types of pneumo- ‘t
cocci and in other species of disease~producing bacteria as well. Because
of this unusual distribution it was thought that cellobiuronic acid, a |
substance no more complex in chemical structure than common table sugar,
might have an important {mmuno~chemical function. That this ie so can
be seen from the following account.

Unlike the immunologically active complex polysaccharide from a
which it is derived, the simple sugar cellobiuronic acid 4s devoid of any

demonstrable serological activity. Yet by chemical synthesis 4t is pos-

 

sible to combine cellobiuronic acid with a protein to yiold an artificial
complex which when injected into rabbits renders these animals immune to

infection with Type III pneumococci. Moreover the serum of these immune

 

 
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51

rabbits when introduced into mice protects them against infection with
living virulent pneumococci. In addition, the antiserum to this arti-
ficial antigen possesses the remarkable property of protecting mice
against several other types of pneumococcal infections as well. The po-
tency of the serum produced by the immunization of rabbits with this syn-
thetic cellobiuronic acid antigen compares very favorably with the pro-
tective action of sera produced by standard methods employing the native
bacteria from which this material is obtained.

Although the cellobiuronic acid used in the preparation of the
artificially compounded antigen is derived from the products of hydrolysis
of the specific polysaccharide of Type ITI Pneumococcus, there is no
reason to bolievo that the samo acid obtained from sources remote from
bacteria would not serve equally woll. The aldobionic acids, of which
cellobiuronic acid is but one example, were discovered some years ago in
the laboratories of the Hospital. They have since been found widely dis-
tributed throughout the plant kingdom. The direct chemical synthesis of
two of these acids, gentobluronic and acaciabiuronic acids, has already
been achieved in Dr. Goebel's laboratory, and their use in artificially
compounded antigens is at the present time under investigation.

Thus for the first time in the history of infectious diseases,
4t has been possible with an artificially compounded antigenic substance
containing an aldobionic acid to produce a single serum which has proven
effective in the treatment of more than one type of experimental pneumo~
coccal infection, For those familiar with the field of chemical immnol-
ogy it is apparent that this work may open a new and practical approach

to the prevention and cure of pneumococcal infections in man.

 

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