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, a therapeutic agent developed in the Hospital, yields excellent

reeulte.  Despite the progreee already made, much remains to be learned
concerning many aspocte of the problem. The results of Dr. Qoebel'e work
on the production of an antiserum for pnoumococci by the uso of a synthot-
ic antigen afo vory encouraging, and it is hoped that this work will open
up a now approach to the production of cart&in thorapoutic sora.
     Preparation and uBe of a emthetic antigen in the nroduction Of
antigneumococcal Sara. For a number of yeare 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 dieeasee In man.  Methods were devised for studying the inter-
action of pneumococci and the tieeue of the host, and the resulta were
practically applied in the diagnosis and treatment of this diseaso long

before the chemical nature of the substances involved were known.
     In recent years the contributions of chemistry have added much
to our underetanding of the nature and specificity of these immunity re-

actions. ALS a result of these investigations it has been found that
pneumococci are not all alike, but exhibit among themselves difference@
in biological specificity ae diverse aa though they were members of wholly

unrelated species,  Upon the basis of these differences pneumoaocci halo
been classified into thirty-two sharply defined and specific typos. Those
researches have led to the development of curative sera, derived from the
blood of immunized animals, which have been singularly succeesful in the


49

treatment of the disease in man.

    !l'hat pneumococci are enveloped by a mucilaginous capsular sub-
stance which serves as a protective coating to the microorganisms per-
mitting them to grow and multiply in the invaded host, has been known for

many years.  One of the most significant results of the chemo-immunological
studies carried out In the Hospital has been the discovery that the differ-
entiation of the varioue specific types of pneumococci is dependent upon

chemical differences In their capsular substances.  It has been revealed

that each dietinct type of pneumococcus builds about itself from the me-
dium of Its environment an encapsulating carbohydrate, the molecular ar

chitecture of which la in each instance dlffarent.  Just as one may build
an infinite variety of structures from the game building stones, 80 it ie
possible for each type of pneumococcue to construct an individual and
characteristic capsular polysaccharlde from the same atome of carbon,

hydrogen, and oxygen.  The chemical approach to an understanding of the

differentiation of the various pneumococcal types and their varied blo-
logical behavior resides in the comprehension of this fundamental differ-

ence in the chemical etructure of the oapaular carbohydrate peculiar to

each speclf lc typo. For example, It has been found that the `capsular
polyeaccharide of Type III Pneumaooocus' is a aomplex w&r which in many
respecta beare a striking relationship to cellulose, a eubatance unlvew

sally dlstrfbuted In nature.  Cellulose 36 constituted from atany lnoleculer

of the simple sugar glucose,  `II hich are combined to one another by mean8

of a chemical linkage,  On boiling with acid, cellulose may be broken down

to the simple sugar glucose, or, if the hydrolysle is carried not quite
so far, to a sugar made up of two glucose molecules. Thie latter sugar

is called celloblose,  Now If the terminal, or twelfth carbon atom of


cellobiose is oxidized to an acidic group the sugar-acid "cellobiuronic

acid" is obtained .  It is this substance which constitutes the fundamental

building stone of the complex capsular carbohydrate of the Type III Pneumo-

coccus.

     When the capsular polysaccharide of Type III Pneumococcus io
isolated in pure form it is found to be devoid of certain immunological
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 single cellular
constituent of the Type III Pnoumococcue with a protoin to yield an ar-
tificial substance, which when lnjocted Into rabbits is capable of in-

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citing specific imity to infection with virulent homologous organisms.
     Cellobiuronic acid is found not only in the capsular polysaccha-

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                   but it and other closely related sugar   1 `I
                                                                           :
ride of the Type III Pneumococcus,                                                           i :
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acids are present In the specific carbohydrates of other types of pneumo-
cocci and in other species of disease-producing bacteria as well. Because

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of this unusual distribution it was thought that cellobiuronic acid, a
substance no more complex In chemical structure than common table sugar,

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might have an important lmmuno-chemical function.  That this is so can           j II
                                                                           I ii
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be seen from the following account.
    Unlike the immunologically active complex polysaccharide from

which it Is derived, the simple sugar cellobiuronic acid is devoid of any

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demonstrable serological activity.  Yet by chemical synthesis it ia pOS-            ! ,
                                                                           L

sible to combine cellobiuronic acid. with a protoin to ylold an artificial
complex which when injected into rabbits renders these animals imi1R2IN to

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


333-f

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 pod

tency of the sew produced by the immunization of rabbits with this syn-

thetic cellobluronic acid antigen compares very favorably with the pro-

tective action of sera produced by standard methods employing the native

bacteria from nhfch this material Is obtained,

Although the cellobluronic acid used in the preparation of the

artificially compounded antigen is derived from the products of hydrolysia

of the specific polysaccharido of Type III Pneumococcus, there Is no

reason to bolievo that the sama acid obtainad from sources remote from

bacteria would not servo equally ~011. The aldoblonic aolde, of which

cellobiuronlc acid is but one example, were discovered some years ago in

the laboratories of the Hospital.  They have since been found widely die-

tributed throughout the plant kingdom.  The direct chemical synthesis of

two of these acids, gentobiuronlc and acaciabiuronic acids, has already

been achieved in Dr. Gosbelle laboratory, and their use in artificially

compounded antigens is at the preeent time under investigation.

     Thus for the first time In the history of infectious diseases,

it has been possible with an artificially compounded antigenio 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 immunol-

ogy it is apparent that this work may open a new and practical approach

to the prevention and cure of pneumococcal infections in man.