Detection of donor-derived cells by polymerase chain reaction in neonatally tolerant mice. Microchimerism fails to predict tolerance.
Although it has long been appreciated that establishment of chimerism is important in the acquisition and maintenance of allograft tolerance, the importance of this relationship has been reemphasized recently. Using the exquisite sensitivity of the polymerase chain reaction we have studied qualitatively and quantitatively the presence of donor-derived chimeric cells in relation to the ability of neonatally injected mice to display skin graft tolerance or rejection. We have found that virtually all mice that receive neonatal injections of F1 hematopoietic cells acquire donor-derived chimerism that is detectable in blood, spleen, lymph nodes, and thymus. Surprisingly, neither the presence nor the quantity of chimeric cells predicts whether a particular neonatally injected mouse will accept or reject donor-specific skin allografts. Moreover, whether the test skin allograft is accepted (tolerance) or rejected by neonatally injected mice, chimerism typically remains detectable within recipient lymphoid tissues. In functionally tolerant mice, challenge with a test skin allograft actually leads to a remarkable expansion in donor-derived genetic sequences, implying that donor-derived cells have been induced by the graft to undergo proliferation. Since persistence of chimerism without proliferation after test grafting is characteristic of mice that fail to display tolerance, we believe that achievement of a threshold level of donor-derived alloantigen may be necessary to retain the tolerant state. We conclude that chimerism is essential for the induction of neonatally induced tolerance, and its expansion may play an important role in the maintenance of that tolerance, when challenged by an allograft.
D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D001483:Base Sequence; D002678:Chimera / Q000276:immunology*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous; D014998:Y Chromosome