Tobacco Documents Online

TSE COUNCIL FOR TOBACCO RESEARCH-U.S.A., INC. Memorandum To: Dr. J.F.Glenn and Staff From: D.H.Ford Re: Site visit with Dr.L.J.Wysucki, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO, Oct.10, 1990. Grant No. 2419 entitled "Immunogenicity of peptide fragments." Goal: To determine if immunodominant peptides (with respect to T-cell stimulation) can replace complex carrier proteins that mediate T-cell- dependent antibody responses. Or, as otherwise stated: can B-cells be induced to mutate their V regions in vitro when stimulated by a route that more directly stimulates the presumed events which occur in vivo in response to T-cell-dependent antigens. Results:As expressed in his recent progress report, Dr. Wysocki has begun to exploxein vitro a polyclonal model of B-cell activation to identify the lymphokines produced by T-helper cells which promote antibody synthesis, isotype switching and somatic mutation. He has produced B cell hybridomas which demonstrate that B cells switch to the production of IgG and IgE isotypes. Further studies using a DNA probe derived from a kappa variable gene have revealed that the ex- pressed Vk genes lack somatic mutations. This observation supports the in vivo data which indicates that switching and somatic mutation processes are separately controlled and that prolonged stimulation of B-cells alone is insufficient to induce somatic mutation. He infers that somatic mutation in B-cells is independent of T-cell-dependent isotype switching and apparently tightly controlled in vivo.A man- uscript entitled "Ia-mediated proliferation and isotype switching of B-cells does not lead to somatic mutation in vitro," (This paper acknowledges CTR)j has been submitted. Comments and Discussion: From the amount of information presented by Dr. Wysocki, it is apparent that he and his colleagues have been very busy." Collectively, they represent a young, enthusiastic well informed- group of investigators. Simply stated, their primary interest appears to be to determine the mechanisms whereby T-helper-cells help B-cells make antibodies. Further, to what degree do B-cell genes undergo changes (rearrangement/mutation/etc.) in re-sponse to exposure to a strange antigen to induce a mutation which can produce an antibody to this antigen? How many antibodies can a B-cell family produce? Theoretically, 109, based on the number of gene sequences believed to be present in a mammalian cell. However, it is not known as yet what exactly are the limits of the creation of B-cell memory for antibody production.For me this was an extremely interesting and informative visit which furthered my understanding of the immune response. The work from this laboratory is well focussed and relevent to the goals of CTR. DHF