Immunity and Pathogenesis of Third World Diseases: Leprosy and Tuberculosis 
autoimmune disease and increasing transplant 
survival. 
We have learned that the unresponsiveness in 
leprosy is antigen-specific-, lepromatous leprosy 
patients unable to respond to antigens of M. le- 
prae usually respond to those of M. tuberculosis, 
which is a closely related mycobacterium. How is 
it possible for T cells to recognize antigens in the 
tubercle bacillus and yet be unable to recognize 
the same or closely related antigens associated 
with the leprosy bacillus? We proposed that there 
might be one or a few unique antigens associated 
with M. leprae that induce active T cell suppres- 
sion of potentially reactive T cell clones. Sup- 
pressor cells in immunology have been a contro- 
versial subject, but the idea that some T cells can 
down-regulate immune responses, particularly 
self-destructive ones, is compelling. About 85 
percent of patients with lepromatous leprosy 
have a subset of T cells capable of being triggered 
specifically by leprosy antigens to suppress re- 
sponses of immune T cells. Although they repre- 
sent a minor subset of T cells in the blood, they 
are the major lymphocyte subset in lepromatous 
lesions. By establishing long-term T cell clones 
directly from the lesions and blood, we found 
that the suppressor cells have a pattern of antigen 
recognition different from other cytotoxic or 
lymphokine-producing T cells. They carry the 
surface marker CDS and recognize foreign anti- 
gens in association with the HLA-DQ region of the 
human major histocompatibility complex (MHC) 
class II. We speculate that presentation of anti- 
gens by this MHC subset predisposes the immune 
responses toward negative rather than positive 
responses. Our studies suggest that functionally 
distinct subsets of T cells are characterized by 
distinct patterns of lymphokines produced upon 
antigenic stimulation. 
New Vaccines from Old — Recombinant BCG 
as a Multivaccine Vehicle 
Vaccines represent the most cost-effective med- 
ical intervention. Yet three general problems 
limit the use of many current vaccines: 1) they 
require multiple booster shots to be effective; 2) 
they cannot be given for 6-12 months after birth, 
because of transferred maternal antibodies that 
inactivate them; and 3) the cost. BCG (bacille 
Calmette-Guerin) , the most widely used vaccine 
in the world, is a live, attenuated bovine tuber- 
cle bacillus given to protect children against 
tuberculosis. 
BCG has been given to more than 2.5 billion 
people and has a very low incidence of serious 
side effects. It is one of only two childhood vac- 
cines that can be given at birth or any time there- 
after. It is a single-shot vaccine that engenders 
long-lasting cellular immunity and costs only 
$0.10 a dose. 
The unique attributes of BCG suggested to us 
that, if it could be genetically engineered to ex- 
press a variety of foreign antigens protective for 
different pathogens, a single immunization might 
be capable of engendering protective responses 
to multiple pathogens simultaneously. One prob- 
lem, however, was the paucity of molecular ge- 
netic information about the Mycobacteria. In col- 
laboration with William Jacobs (HHMI, Albert 
Einstein College of Medicine), we developed ge- 
netic systems for introducing and expressing for- 
eign genes in mycobacteria, particularly BCG 
strains. We developed a shuttle strategy in which 
mycobacterial DNA could be genetically cloned 
and manipulated in E. coli and then transferred 
into mycobacteria. Our first approach was to use 
mycobacteriophages (viruses that infect bacte- 
ria) as vectors to target foreign genes to a specific 
site in the bacterial chromosome. This enabled us 
to introduce foreign DNA into BCG for the first 
time. Recently we have developed shuttle plas- 
mid vectors that are able to produce many copies 
of foreign genes in BCG. 
With several collaborators at Medlmmune, 
Inc., and the University of Pittsburgh, we have 
developed the first experimental recombinant 
BCG vaccines. These express protective antigens 
from M. leprae, schistosomes, malaria, measles 
virus, leishmania, and HIV. Initial experiments in 
mice indicate that three major types of protective 
immune responses can be generated in vivo — 
namely immunoglobulin antibodies, T cell lym- 
phokines, and cytotoxic T lymphocytes. Continu- 
ing efforts will be made to define antigens that 
will engender, through recombinant BCG, pro- 
tective immunity against a variety of viral, bacte- 
rial, and parasitic pathogens. 
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