[Genetic control of humoral immune response to xenografts. A monoclonal antibody that causes the hyperacute rejection of cardiac xenografts uses the genes in a native form].

The early phases of the rejection of xenografts exchanged between closely-related species are dominated by a vigorous humoral immune response. We have recently used a linkermediated polymerase chain reaction to generate Ig heavy and light chain specific cDNA libraries to examine the Ig gene control of a prototypic IgM monoclonal antibody, HAR-1, that causes the hyperacute rejection of hamster xenografts. Recombinant clones from the library were screened directly from bacterial colonies by PCR and the nucleic acid sequences of the clones established. Our results demonstrate that the HAR-1 hybridoma is encoded by Ig VH and JH genes in a germline configuration. Comparison of the cDNA sequence for HAR1-VH with the germline equivalent of the gene isolated from newborn LEW liver (provisionally designated VH1.1) showed that the two VH sequences share a nucleic acid identity of 99,3%. Similarly, the HAR-1 monoclonal uses a Ig JH gene that is 98,2% identical with the JH1 nucleic acid sequence available in the GenBank. The use of Ig VH and JH genes in a germline configuration is similar to that seen with polyreactive natural antibodies to infectious agents and autoantibodies. These humoral responses are thought to be the results of the stimulation of a T cell-independent subset of B cells, the B-1a/B-1b subset, that are responsible for producing antibodies that serve as a primitive humoral (natural antibody) defense mechanism against infectious diseases. Our results suggest that the humoral component of the rejection of xenografts in the hamster-to-rat model may represent the stimulation of this type of B cell antibody response by xenogeneic target antigens that share antigenic epitopes with bacteria and other infectious agents.