Jpn. J. Infect. Dis., 52, 1-11, 1999


Review
How BCG Led to the Discovery of Immunostimulatory DNA

Tohru Tokunaga * , Toshiko Yamamoto 1 and Saburo Yamamoto1

Fukuoka Jo-Gakuin University, 3-42-1, Osa, Minami-ku, Fukuoka 811-1313, and
1 Department of Bacterial and Blood Products, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011, Japan

(Received November 16, 1998. Accepted December 22, 1998)

CONTENTS:
1. Introduction
2. The finding of antitumor activity of DNA from BCG
3. The mode of antitumor action of BCG-DNA 
4. The finding of particular base sequences in BCG-DNA which is required 
   for immunostimulation
5. The finding of that DNA from bacteria, viruses and invertebrates, but not
   from vertebrates and plants, activate immunocytes of mouse and human 
6. The toxicity and pharmacology of BCG-DNA 
7. The clinical trials with BCG-DNA 
8. The present status of immunostimulatory DNA studies 
    i )   The immunostimulatory sequences 
   ii )   The activities of immunostimulatory DNA 
   iii)   The intracellular mechanisms of action 
    iv)   The immunostimulatory DNA as immunoadjuvants for vaccines 
     v)   The therapeutic applications of immunostimulatory DNA 
    vi)   The role of immunostimulatory DNA in disease pathogenesis 

SUMMARY: The concept of immunostimulatory DNA was borne in a long series of 
studies on BCG-mediated tumor resistance.  DNA purified from BCG inhibited the 
growth of various syngeneic animal tumors, augmented NK cell activity and induced
IFN-ƒΏ/ƒΐand -ƒΑfrom mouse spleen cells and human PBL. Extending the lines of 
study, we found two biologically remarkable facts that (i) DNAs from invertebrates, 
but not from vertebrates and plants, showed the above-mentioned biologic activities,
and (ii) the activities were completely dependent on particular base sequences having
CpG motifs but in a senseless manner. Details of those early studies carried out mainly 
in the 1980's have been reviewed in the first part of this paper. In the middle part of 
this review, the results of toxicity and pharmacology studies and clinical trials of BCG-
DNA, performed by other groups in Japan in the late 1980's, were introduced. Since 
a large amount of DNA had never been administered repeatedly into experimental 
animals or human, those experiences obtained seem to be worthwhile to introduce. 
Research interests of immunostimulatory DNA were galvanized in 1995 by the report 
of Krieg et al. showing murine B cell activation with bacterial DNA containing CpG 
motifs. Within a short period of time, a huge number of papers have been published in 
this field, and the study has expanded rapidly and largely. Now, it includes a number of 
research fields, for example, host-defense mechanisms against infection, allergy, 
autoimmune diseases, cytokine networks, plasmid vaccination, and therapeutic application 
of certain diseases. This paper reviewed briefly recent advances of immunostimulatory 
DNA research. The response of higher animals against immunostimulatory DNA must be 
the most primitive but important mechanism for self-nonself discrimination against foreign 
DNA.  By utilizing immunostimulatory DNA or controlling this primitive response, it seems 
possible to offer many beneficial means to human health. For instance, more potent
peptide- or plasmid- vaccines could be developed by the use of immunostimulatory DNA. 
On the other hand, many study results suggest that immunostimulatory DNA works either 
beneficially or harmfully for the hosts. We assume that further extensive and careful 
studies are required.



*Corresponding author: Tel: +81-92-581-1492, Fax: +81-92-575-2480
  E-mail: tokunaga@fukujo.ac.jp


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