PART 11. IMMUNOLOGICAL TOLERANCE TO GRAM-NEGATIVE BACTERIA~ELLULAR AND HUMORAL ASPECTS

INTRODUCTORY REMARKS TO SESSION 2

Jan Cerny

Microbiology Department Albert Einstein Medical Center

Philadelphia, Fa.

I shall attempt to summarize briefly the complexity of immunological unresponsiveness as it is induced by a wide range of antigen concentrations. I will emphasize several points, some of which will be discussed by other speak- ers and which should provide us with a common background for discussion.

The effect of stimulation with different antigen doses can be evaluated either by measuring the primary response or by assay for secondary responsive- ness, using an immunogenic challenge ( FIGURE 1 ). A very low antigen concen- tration has been found that does not elicit detectable serum antibody synthesis but induces an immunological “memory,” i.e., a typical secondary response is observed after challenge.’, In The critical proof of this priming effect without an immune response is still missing on the level of antibody-forming cells (AFC) . As the initial antigen concentration is increased, a “low dose” tolerance may be induced that is manifested as suppressed responsiveness to the second challenge, instead of a priming.21 *a It seems, however, that this tolerance status may already be accompanied by an immune response elicited by the initial stimulus, as indi- cated on the level of AFC.3 Does this mean that an unresponsiveness is induced initially with an antigen concentration range that is capable of inducing anti- body synthesis? This point will be discussed more generally by Dr. Diener.

Still further, increase of the primary antigen dose leads to a more vigorous primary antibody response, which is again accompanied by presensitization to secondary challenge. This continues until an “exhaustion” is reached when the maximal primary response is followed by a relative unresponsiveness to ~hal lenge .~ Here, too, both antibody synthesis and tolerance appear to occur together. Finally, the initial or primary antigen concentration may reach a point where no antibody response is induced and no AFC differentiation occurs,6-T i.e., “high dose” tolerance or paralysis. Cells must be exposed to the paralyzing antigen concentration for some time to obtain a relatively long- lasting unresponsiveness to challenge. Some data indicating possible presence of competent antigen-reactive cells in paralyzed animals will be presented subsequently.

It should be realized that for two different antigens, and especially for two determinants of the same complex antigen, the dose-response curve shown in FIGURE 1 may fall into quite different areas. For example, after immunization with a given dose of a complex bacterial antigen, there may be a partial toler- ance induced to determinant A and good immune response elicited to determi- nant B. If the assay method used involved the determinant A only, immuno- logical tolerance would be detected to the whole complex, and vice versa. Some results suggesting that this may be the case will be presented by Dr. Allen. There is also some more direct evidence available in our laboratory from experiments by Dr. Sajid and coworkers concerning this problem.8 Undoubtedly,

78

Cerny: Introductory Remarks to Session 2 79

"PRIMING"

I T SECONDARY

- "PRIMARY" DOSE OF ANTIGEN

FIGURE 1. Immunity and tolerance induction with different antigen dosages.

similar questions will be raised also in connection with the experiments demon- strating the absence of AFC and simultaneous presence of rosette-forming cells during "high dose" tolerance.

References

1. NOSSAL, G. J. V. et a!. 1965. Immunology 9: 333. la. VALENTOVA, V. et al. 1966. Folia Biol. (Prague) 12: 207. 2. MITCHISON, N. A. 1964. Proc. Roy. Soc. B. 161: 275. 2a. SHELLAM, G. R. & G. J. V. NOSSAL. 1968. Immunology 14: 273. 3. ALLEN, J. L. & H. FRIEDMAN. 1969. Fed. Proc. 28: 2845 (abstr.). 4. STERZL, J. 1966. Nature (Lond.) 209: 416. 5. SERCARZ, E. E. & A. H. COONS. 1963. J. Immunol. 90: 478. 6. CERNY, J. & J. IVANYI. 1966. Folia Biol. (Prague) 12: 343. 7. DIENER, E. & W. D. ARMSTRONG. 1967. Lancet 7529: 1281. 8. SAJID, M. A., R. MCALACK, J. CERNY & H. FRIEDMAN. 1971. J. Immunol. In

press.