Immunity and Pathogenesis of Third World Diseases: Leprosy and Tuberculosis 
triggered specifically by leprosy antigens to sup- 
press responses of immune T cells. Although they 
represent a minor subset of T cells in the blood, 
they are the major lymphocyte subset in leproma- 
tous lesions. By establishing long-term T cell 
clones directly from the lesions, we found the 
suppressor cells to have a unique pattern of anti- 
gen recognition different from other cytotoxic or 
lymphokine-producing T cells. They carry a par- 
ticular surface marker, CDS, and recognize for- 
eign antigens in association with a particular 
region, HIA-DQ, of the human major histocom- 
patibility complex (MHC), class II. We speculate 
that presentation of antigens by this MHC subset 
predisposes the immune responses toward nega- 
tive rather than positive responses. We hope to 
understand the molecular basis of T cell 
suppression. 
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 current vaccines: 1) they require 
multiple booster shots to be effective; 2) they 
cannot be given for 6-12 months after birth, be- 
cause of transfer of maternal antibodies that inac- 
tivate them; and 3) the cost. BCG (bacille Cal- 
mette-Guerin) is the most widely used vaccine in 
the world. It is a live, attenuated bovine tubercle 
bacillus given to protect children against tuber- 
culosis. Studies by our collaborator, Jacinto Con- 
vit, in Venezuela, revealed that immunologically 
unresponsive patients with lepromatous leprosy 
could be converted to positive cell-mediated im- 
munity and often self-cure by injection of a mix- 
ture of killed M. leprae together with BCG vac- 
cine. This represents the first instance of vaccines 
being used therapeutically. It is also the first ex- 
ample of patients overcoming a specific immuno- 
logic tolerance, and indicates that BCG is a potent 
human immune enhancer, or "adjuvant." 
BCG has other unique attributes as well. It has 
been given to over 2.5 billion people and has a 
very low incidence of serious side effects. It is 
one of the few childhood vaccines that can be 
given at birth, or any time thereafter. It is a single- 
shot vaccine that engenders long-lasting cellular 
immunity and costs only six cents 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 undertook to 
develop new genetic systems for introducing for- 
eign genes into mycobacteria, particularly BCG 
strains. We developed a shuttle strategy in which 
mycobacterial DNA could be genetically cloned 
and manipulated in E. coli, then transferred into 
mycobacteria. Our first approach was to use my- 
cobacteriophages (viruses that infect bacteria) as 
vectors to target foreign genes to a specific site in 
the bacterial chromosome. This enabled us to in- 
troduce foreign DNA into BCG for the first time. 
Recently we have developed shuttle plasmid vec- 
tors that are able to produce many copies of for- 
eign 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, E. coli, schistosomes, malaria, 
leishmania, and HIV (human immunodeficiency 
virus). Initial experiments in mice indicate that 
three major types of protective immune re- 
sponses can be generated in vivo — namely, im- 
munoglobulin antibodies, T cell lymphokines, 
and cytotoxic T lymphocytes. Continuing efforts 
will be made to define antigens that will engen- 
der in recombinant BCG protective immunity 
against a variety of viral, bacterial, and parasitic 
pathogens. 
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