Humoral factors in canine renal allograft rejection.

D. S. Clark, J. E. Foker, R. A. Good, R. L. Varco

Research output: Contribution to journalArticlepeer-review

15 Scopus citations
Original languageEnglish (US)
Pages (from-to)8-10
Number of pages3
Issue number7532
StatePublished - Jan 6 1968

Bibliographical note

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also present within the glomeruli. The interstitial infil- tration was usually accompanied by significant interstitial haemorrhage. One biopsy specimen taken 4 hours after reimplantation to A showed a very heavy infiltration by polymorphs and virtual destruction of the peritubular capillaries (fig. 3a). The tubules themselves showed greatly increased (although often patchy) damage. Tubular cells were swollen to the point of obliteration of the lumens and cellular outlines were frequently disrupted. Second biopsy specimens obtained 6-13 hours after reimplantation showed further deterioration of kidney structure; large areas of tubule cells were disrupted with varying degrees of nuclear disintegration. Interstitial hxmorrhage remained, but the character of the leucocytic infiltration had changed to one with a predominance of round cells and relatively few polymorphs (fig. 3b). The glomeruli, which had been relatively spared in the earlier specimens began to show some loss of normal architec- ture in the loops and occasional hxmorrhage into Bowman’s space. Three of the kidneys were left in place 16-22 hours, despite cessation of urinary flow. Final sections showed widespread destruction, including disruption of many glomeruli. Round cells prevailed in the leucocytic infiltration with accumulations particularly prominent at the vascular poles of the glomeruli. Mitoses were also seen frequently. Kidneys passed through irradiated hosts not specifically sensitised to them and then reimplanted into their donors (C) gave a different histological picture. Two kidneys showed little change between biopsy specimens taken while in dog B and specimens taken after 24 hours in dog C (fig. 4). Only occasional scattered polymorphs and round cells had appeared. There was no accumula- tion of these cells nor accompanying tubular damage. The third kidney was removed by the dog itself after 48 hours. Sections of this kidney, although showing a great deal of hxmorrhage, had little white-cell infiltration. Discussion Our results demonstrate that humoral factors can initiate an immunological process which results in a dog rejecting his own kidney. The importance of antibodies in allograft rejection has hitherto been diffiicult to assess. Terasaki et al. (1962), using the admittedly traumatic method of infusing strain-specific antiserum directly into the renal arterv in mice obtained transient functional and histological evidence for kidney damage. Other experi-ments demonstrating an effect of passive transfer of sensitised serum have measured only the accelerating effect on the rejection of allografts. In such a system, the primacy of cell-to-cell allogeneic elimination cannot be excluded. Our model, by perfusing the kidney in a sensitised but white-cell-free environment and returning it to the original dog, virtually eliminates this possibility. Therefore, once the initial recognition phase has passed, allografts can be rejected in a system where the only sensitised components are humoral. Sensitised cells appear to be unnecessary. Nelson (1961) suggested that in allogenic combinations (where antigenic disparity may be slight and cross- reactivity expected) antibodies against the graft were cytophilic for host circulating cells. On encountering the graft, the antibodies would gravitate towards it because of greater specificity, and thus would not be found free in the serum. This experiment indicates only that delivery by the host cells is not necessary. Cytophilic antibodies could still be participating after their release from leucocytes damaged by irradiation. Our demonstration that humoral components can precipitate an allograft rejection does not lessen the importance of the cellular infiltration seen in the usual process of rejection but does suggest that most of its activity may be non-specific. It is difficult to escape the conclusion that in our model the dog’s own cells were responsible for the rapid rejection of its kidney. The gross features of renal allograft rejection-decreased urinary output, increased size, and decreased blood-flow- correlated well in time with the interstitial infiltration of polymorphs and platelets. Reacted complement and other chemotactic substances probably account for the presence of these cells. Their infiltration and the vascular damage may depend upon their reactivity as shown in the Arthus reaction by Stetson (1951). Presumably the action of antibody and complement alone on the allograft cell membranes would be disruptive. However, the extent and functional consequences of this was not determined in this experiment. Nor did it throw light on the nature of the humoral factors involved. The important elements may not be conventional antibody. This experiment and related work provides an oppor- tunity to present a unified concept of the renal allograft reaction. An allografted kidney by 3 days will have stimulated immunologically competent cells to produce, without further division, humoral factors which are completely sufficient to cause an intact animal to reject its own kidney. Whether antiserum and complement alone are sufficient to damage the graft irreversibly remains uncertain. Nevertheless, these sera will initiate a typical allograft reaction where no cellular allogeneic incompatibility exists. The reaction of humoral factors and the graft produces chemotactic substances which rapidly call forth infiltrating cells. The cells which arrive first and appear to accomplish much of the rejection in this model are polymorphs and platelets, which are recognised to be immunologically non-specific. Last to appear in our experiment were the mononuclear cells which, in the unmanipulated allograft, would first recognise the foreign tissue, produce antibody-like substances, and initiate the sequence of renal graft rejection. We thank Mr. Arthur LeDoux and Miss Laurie Reinhart for technical assistance. The work was supported by U.S. Public Health Service Grant GMO 4778-10. Requests for reprints should be addressed to R. L. V., department of surgery, University of Minnesota Medical School, Minneapolis, Minnesota 55455, U.S.A.

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