Immunology Today, vol. 6, No. 10, 1985

Lymphocytes handled in v/tro do recirculate from blood to lymph SIR, In his article, (Immunol. Today 1985, 6, 149-152), Joe Hall points out all the pitfalls when interpreting experiments on in-vivo behavior of lymphocytes radiolabelled in vitro and then injected into animals by various routes. A lucid demonstration of this was recently published in a series of papers by Marilyn Smith and Bill Ford ~, who showed that thoracic duct lymphocytes that had been collected at 4°C over several hours before intravenous (iv) injection recirculated much more sluggishly than did cells subjected to minimal handling in vitro before injection. W e therefore entirely support Hall's emphasis on the caution that must be exercised when trying to extrapolate from such experiments to the precise migratory behavior in vivo of cells undisturbed by the experimenter. However, although Smith and Ford' s critical work has subjected to reinterpretation much of the quantitative data on lymphocyte recirculation, no one would today question the principal theory that a large n u m b e r of both T and B lymphocytes do recirculate, a theory that after all was constructed on the basis of experiments requiring extensive handling of the cells in vitro. Despite his eloquent warning, Hall no doubt agrees with us that the study of in-vivo migration patterns of circulating lymphocytes handled carefully in vitro has provided a wealth of

This letter was shown to Professor Hall, who replied as follows: SIR, Due to limitations on space, the article I wrote was couched in general terms, and so many of the statements I made will fail when applied to particular cases. Although the title concerned lymphocytes, I did not intend my remarks to exclude other cell types. It is true that in rodents heat-killed small lymphocytes are not held up or destroyed to any great extent in the lung after intravenous (i.v.) injection; as Rolstad and Fossum point out, they are dealt with mainly in the liver. However, larger cells such as immunoblasts, tumour cells, and granulocytes are dealt with to a considerable extent by the lungs, as are glutaraldehyde-fixed small lymphocytes. In sheep, even isologous, healthy (but ~lCr-

289 valuable information on the in-vivo behavior of both T and B cells, data that fit with the observed distributions of both T and B cells in blood, lymph, and in the various lymphoid tissues in a steady state. O u r first point here concerns Hall's reflections on the role of the lung in lymphocyte migration studies. We believe that the sequestration of cells in the lung probably has a meaning other than the removal of effete cells from the circulation. Hall himself provides arguments for this by referring to data where intra-arterially injected ceils showed the same entrapment in the lungs as did i.v. injected cells. We hesitate with believing that the lungs serve as a graveyard for effete cells, and our disbelief is supported by experimental data. By autoradiography we have observed transient sequestration of intact labelled lymphocytes within the alveolar walls of the lungs ½ h after i.v. injection of the cells. By 24 h, most of these cells are no longer detectable in the lungs, and there is no evidence of destruction of labelled cells here. Furthermore, heat killed cells or allogeneic cells injected i.v. into presensitized recipients, are trapped, not in the lungs, but in the liver 2'3. This organ is more likely to represent the lymphocyte graveyard u n d e r the circumstances imposed by the experimental conditions. O u r second and main point, however, is the way Hall has interpreted our findings on the rapid rejection of allogeneic lymphocytes in nonsensitized recipients +. These cells are rapidly killed within the lymph nodes and spleen, and then phagocytosed and broken down by

interdigitating ceils situated within the T-cell areas in these organs (Ref. 5 and unpublished observations). We share Hall's view that this mechanism did not evolve to deal with allogeneic cells, but his assumption that the mechanism is responsible for removal of 'effete self' completely lacks experimental support. O n the contrary, in the experiments he referred to, we examined extensively lymphoid tissues of athymic rats given iv injection of from 100 to 200 x 106 [3H]uridine labelled syngeneic lymphocytes. The n u m b e r of interdlgitating ceils with radiolabelled nuclear fragments in their cytoplasm was close to zero. In conclusion, it is possible to interpret resuks from lymphocyte migration experiments in vivo, provided that Gowans' rules are followed as far as is practical, and that the experiment is Controlled, e.g., by including cells with a known tissue distribution, Nevertheless, care should always be taken when trying to infer from such experiments the quantitative distribution of cells in the steady state. []

labelled) small lymphocytes are trapped in the lung and destroyed. This perhaps reflects the more 'active' maerophages of animals living in a normal, unprotected environment, and also the fact that even the 'small' lymphocytes of sheep are significantly larger than the corresponding cell in the rat. In sheep, also, some of the large lymphoid immunoblasts seem to have a physiological role in the lung, and so their apparent 'trapping' after i.v. injection may merely be physiological extravasation. In such large animals it is very difficult to do autoradiographic studies that could show the exact localization of the infused cells so there are still many gaps in our knowledge. However, in this species it is easy to find, in both adult and prenatal animals, that the dendritic cells in peripheral tissue fluid often contain engulfed lymphocytes. Whether these

cells were engulfed because they were effete or because they were supernumerary or of an anti-self specificity is unknown. I have always believed that the excess of lymphocytes that are produced in the thymus or (in sheep) in the bursal-equivalent Peyer's patches were destroyed locally, rather than later in the lymph nodes, but this is only a feeling based on received opinion rather than personal experimentation. The fate of allogeneic lymphocytes cannot be investigated easily in crossbred sheep. It is obviously a fascinating topic where strain differences may be important. ~.~


Anatomical Institute, University of Oslo, Oslo, Norway. References 1 Smith, M. E. and Ford, W. L. (1983) Immunology 49, 83-94 2 Heslop, F. and Hardy, B. E. (1971) Transplantation 11, 128-13+ 3 Bainbridge, D, R., Brent, L. and Gowland, G. (1966) Transplantation 4, 138-153 4 Ford. W. L., Rolstad, B. and Fossurn, S. (1984) Immunol. Today 5, 227-228 5 Fosaum, S., Rolstad, B. and Ford, W. L. (1984) Imrnunobiology 168, 403-413


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