Evidence for Actively Acquired Tolerance to Rh Antigens

Abstract

Billingham et al. [1] reported that mice and chickens injected as embryos with cells from other strains acquired a persistent tolerance to later skin grafts from the donor strains. It seemed possible to us that a similar, but naturally acquired, tolerance might be in part responsible for the variation in response of Rh-negative persons exposed to the Rh antigens. [2] The hypothesis to be tested was that Rh-negative children of Rh-positive mothers might, as a result of their exposure as embryos to the maternal Rh antigen, acquire a degree of persistent tolerance toward the antigen. Rh-negative children of Rh-negative mothers, on the other hand, could have had no similar embryonic exposure and might therefore be expected to react more easily upon encountering an Rh-positive antigen in later life. We have collected data on the mothers of two groups of Rh-negative women: first, those in whom there is no evidence of Rh sensitization within three Rh-positive pregnancies and, second, those who have developed evidence of Rh sensitization during or before their third Rh-positive pregnancy. The first-group we classify as relatively "tolerant" and the second as relatively "intolerant" to Rh antigens. Table 1 lists the Rh types of the mothers of women in these two groups. A simple χ^2 test for homogeneity yields a probability of less-than 0.01 that the two samples of mothers could have been drawn by chance from the same population. In other words, these data seem to offer good reason to believe that the degree of Rh tolerance displayed by Rh-negative women is indeed related to their mothers' Rh types. A number of cases included in the study have been omitted from Table 1 because of uncertainties in their classification. For example, stillbirths or miscarriages of unknown Rh type made it impossible to classify some of them according to the criteria of tolerance we have employed. Some of the data that are included in Table 1 are open to question on other grounds. Ten of the women were given transfusions or injections of blood at some time prior to their third Rh-positive pregnancy. Some of these transfusions were with Rh-positive blood, others with blood of unknown Rh type, and others probably with Rh-negative blood. Two additional women believed that they might have received injections or transfusions of blood but were not certain that they had. It is difficult to evaluate the number of exposures of these twelve women to Rh antigens or to weigh the sensitizing significance of blood injections or transfusions relative to the importance of an Rh-positive pregnancy. Table 2 lists the data after the exclusion of all cases in which there is a record suggesting that blood may have been transfused or injected. A χ^2 test for homogeneity on the data of Table 2 yields a probability of less than 0.001. It should be noted that transfusions or injections with Rh-positive blood appear to provide a very effective stimulus to Rh sensitization and that a considerable number of the Rh-negative daughters of Rh-positive women who fall in the "intolerant" class have been stimulated by this route.

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