Immunomodulation - an idea from the past looks more promising than ever
Thomas C. Jones
In this issue of the BJID the case report by Badaró, et al. reminds us again of the potential for the human immune system to overcome pathogenic processes, assisted by some new ideas from the fields of biological science and medical care. Stimulation of the immune response to control disease is quite an ancient approach to medical care, side-tracked during the time of our fathers and grandfathers by the development of the magic bullet against microbial disease and cytotoxic chemotherapy against malignant processes. Over 100 years ago microorganisms were injected into patients in an attempt to cure malignant diseases [1], or to treat infections such as syphilis by inducing fever [2, 3]. The process of blood letting [4], modified in Brazil (as reported to me by Dr. Heonir Rocha) by re-injecting the removed blood subcutaneously, was certainly a potent form of cytokine stimulation. Other forms of non-specific immune or inflammation stimulants included heavy metals, such as arsenic or mercury [5], in ancient times, and, more recently, leukocyte products (transfer factor) [6], and mycobacteria [7]. The relative successes of these methods are difficult to determine in retrospect, because the science of clinical trials documentation was not yet mature, and because the efficacy of the approaches to antimicrobial therapy and cell-cycle specific chemotherapy were so dramatic, our attention was directed toward specific attack against the microbe or tumor cell. From many different areas we see that the magic bullet approach may no longer be enough. These areas include the emergence of multi-drug resistant organisms and the difficulty of controlling infection in immunologically suppressed patients after cancer chemotherapy or with HIV infection. The emergence of our knowledge of immunology has allowed the medical profession to re-explore these ancient ideas using new tools and with a fresh conceptual understanding [8].
The case presented in this issue of the BJID is particularly relevant to this history because it reminds the reader of the problems in patient care when antimicrobial agents are ineffective or too toxic, as shown to be the case with both the use of amphotericin B and pentamidine. It is also relevant because attempts at general immune stimulation with a mixture of leishmanial antigens presently used in Brazil for immunotherapy [9] was only partially effective, reminding us that the immune system requires a carefully tailored approach. The case moves us into the future by the use of leishmanial antigens which were defined by using the most up-to-date methods, and by the selection among 15 antigens, 4 to which the patient was unresponsive, postulating that it is the mis-direction of the immune response, not its absence, that had led to the continued inflammatory process. It is also relevant that one of the antigens selected, LiEF, has been shown to be one of several leishmanial antigens which has Th1 stimulatory actions [10], to which a newly recognized immunomodulatory cytokine, GM-CSF, was added [11, 12]. The photographs tell the story _ a desperate patient returned to a normal social existence.
Of course, now comes the cautionary note. This is one patient, not a controlled clinical trial, the antigen mixture has not been validated or registered, the role of each component has not been defined. Indeed, whether all of the components (leishmanial antigens, the special leishmanial antigen with adjuvant activity, and GM-CSF) are required is not known. It is my hope that by publishing this case, renewed interest in immunomodulation will be stimulated, and the commitment of time (years) and expense (millions of dollars) will be considered justified. If the result of the publication of this case is only an hysterical scramble to obtain the antigens and adjuvants for other patients, our goal has not been achieved. It is unfortunate, but a reality, that these antigens will not be available for several years to come. This case should stimulate further investment in creative research and thinking, not the obtaining of the specific materials used.
Immunomodulation using up-to-date methods has already become a reality [13]. For example, interferon gamma is used in patients with chronic granulomatous disease [14], interferon alpha is used in patients with lymphoma [15] or chronic hepatitis C [16], IL-2 is used in patients with AIDS [17], and numerous vaccine adjuvants have been developed [18]. The case recorded here of the use of immunomodulation in a patient with mucosal leishmaniasis is an important contribution, by applying recent knowledge of immunology to an ancient method of treatment.
References
1. Coley W.B. The treatment of malignant tumors by repeated inoculation of erysipelas: with a report of ten original cases. Am Jou Med Sci 1893;105:487-511.
2. Roberts J.N. Jr. Impact of temperature elevation on immunologic defenses. Rev Inf Dis 1991;13:462-72.
3. Austin S.C., Stolley P.D., Lasky T. The history of malariotherapy for neurosyphilis. Modern parallels. JAMA 1992;268:516-9.
4. Garrison F.H. The seventeenth century: The age of individual scientific endeavor, in An Introduction to the History of Medicine. W.B. Saunders Co., p. 241-313, 1924.
5. Garrison F.H. The period of the renaissance, the revival of learning, and the reformation (1453-1600), in An Introduction to the History of Medicine. WB Saunders, p.185-240, 1924.
6. Lawrence H.S. Transfer factor in cellular immunity. Harvey Lect 1974;68:239-50.
7. Lugosi L. Theoretical and methodological aspects of BCG vaccine from the discovery of Calmette and Guérin to molecular biology. A review. Tuber Lung Dis 1992;73:252-61.
8. Zinkernagel R.M. Immunology taught by viruses. Science 1996;271:173-8.
9. Genaro O., deToledo V.P., da Costa C.A., et. al. Vaccine for prophylaxis and immunotherapy, Brazil. Clin Dermatol 1996;14:503-12.
10. Webb J.R., Kaufmann D., Campos-Neto A., Reed S. Molecular cloning of a novel protein antigen of Leishmania major that elicits a potent immune response in experimental murine leishmaniasis. J Immunol 1996;157:5034-41.
11. Lin R., Tarr P.E., Jones T.C. Present status of the use of cytokines as adjuvants with vaccines to protect against infection. Clin Inf Dis 1995;21:1439-49.
12. Lin R., Tarr P.E., Jones T.C. Considerations regarding the use of cytokines in active specific immunotherapy of cancer. Vaccine Research 1996;5:41-52.
13. Fauci A.S., Rosenberg S.A., Sherwin S.A., et al. Immunomodulators in Clinical Medicine. Ann Int Med 1987;106:421-33.
14. International Chronic Granulomatous Disease Cooperative Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Eng Jou Med 1991;324:509-16.
15. Engelhart M. Possible role for cytokines in the treatment of lymphoma. In Hemopoietic Growth Factors and Mononuclear Phagocytes, Ed. R. Van Furth, Karger, Basel, p. 177-86, 1993.
16. Davis G.L., Balart L.A., Schiff E.R., et. al. Treatment of hepatitis C with recombinant interferon alpha. A multi-center randomized, controlled trial. N Eng Jou Med 1989;321:1501-6.
17. Davey R.T. Jr, Chaitt D.G., Piscitelli S.C., et. al. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. Jou Inf Dis 1997;175:781-9.
18. Lin R., Jones T.C. Vaccine adjuvants: A new hope for effective immunizations. Braz Jou Inf Dis 1997;1:106-16.
Publication Dates
-
Publication in this collection
20 Feb 2003 -
Date of issue
Aug 2001
