Quantitative studies on tissue transplantation immunity - V. The role of antiserum in enhancement and desensitization

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Abstract
Homografts of all kinds excite the formation of humoral antibodies, but the part played by antibodies in the rejection of skin homografts is still uncertain. Antisera were prepared in mice by the repeated intraperitoneal injection of dissociated lymphoid cells, or by multiple intra-cutaneous injections, on a single occasion, of lymphoid cells incorporated into a myco­bacterial adjuvant. We were unable to discover any circumstances under which the passive transfer of high or low doses of these antisera could shorten the life of freshly transplanted skin homografts in mice (§3). Antisera were equally without effect on skin homografts carried by tolerant mice (§3·3), or by mice in which the primary immune response had been temporarily suppressed by injections of trypan blue (§3·2). Moreover, although lymphoid cells are known to be vulnerable to the action of cytotoxic antiserain vitro, high doses of hyperimmune antisera transfused into tolerant mice were unable to destroy the surviving descendants of the lymphoid cells which had been injected at birth to induce the state of tolerance in the first instance (§3·3). The effect of high doses of antisera on skin homografts, if any, is to prolong their lives (‘enhancement’), but the effect is barely discernible. The enhancing action of antiserum was made most clearly apparent by its power to prevent the development or expression of sensi­tivity inCBAmice which had received injections of cell-free antigenic matter ofA-strain origin (§4).CBAmice which receivedA-strain antigen plus 1·0 ml. hyperimmune anti-Aserum rejectedA-strain skin grafts more slowly than mice which had received normal serum instead of immune serum. It is not likely that the antiserum acted directly upon the antigen, first because the antiserum was just as effective when injected as late as 3 days after the sensitizing dose of antigen (§4·1), and secondly, because the sensitizing power of antigen was not perceptibly reduced by exposure to the same quantity of antiserumin vitrobefore in­jection (§4·2). Nor is antiserum likely to have acted by coating (or otherwise lowering the vulnerability of) the cells of the skin graft used to measure the prevailing degree of sensi­tivity, for passive transfusions of antiserum did not lower the sensitivity ofpresensitized mice (§5). Antiserum probably affects the process of sensitization itself, acting by a ‘central’ inhibition of unknown character rather than by obstructing the afferent or efferent pathways of response (§7·2). Two elementary phenomena relating to the duration and degree of the sensitivity produced by homografts require an explanation, (a) The sensitivity produced in mice by a single skin homograft is still clearly in force 240 days after its transplantation, but the sensitivity produced by a single intraperitoneal injection of 0·125 to 5·0 million lymphoid cells declines to a small fraction of its original value within 20 days (§ 6·1). (b) The repeated injection of high doses of foreign lymphoid cells, though provoking the formation of high titres of haemag-glutinins and haemolysins, does not raise the sensitivity of their recipients: aCBAmouse which has received six weekly intraperitoneal injections of 25 to 125 millionA-strain lymphoid cells rejects anA-strain skin graft less promptly than aCBAmouse which has received a single injection of 5 millionA-strain lymphoid cells 3 days beforehand (§ 6·2). No important fraction of this decline of sensitivity can be attributed to a ‘graft-versus-host’ reaction (§6·2). There is a temptation to believe that the decline of sensitivity that follows or accom­panies single or repeated injections of lymphoid cells is a ‘self enhancement’ attributable to the formation of humoral antibodies, but there are objections to this view, and a number of alternative possibilities are discussed (§§7·3, 7·4).

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