The chronic graft-versus-host disease (cGVHD) in mice is characterized by the production of autoantibodies and immunopathology characteristic of systemic lupus erythematosus (lupus). severe in females as it is in several of the spontaneous mouse models of lupus as well as in human disease. The mechanism of this female skewing of Tmeff2 disease appears to depend on the relative inability of CD8 cells of the female host to downregulate the donor CD4 T cells that drive the autoantibody response. In general then the abnormal CD4 T cell help and the modulating roles of CD8 T cells seen in cGVHD parallel the participation of T cells in genetic lupus in mice and human lupus although these spontaneous syndromes are presumably not driven by overt alloreactivity. or plays a major role in driving the loss of tolerance. However in general the genetic contribution is complex and involves multiple loci which are not yet fully defined . Where the issue of environmental influences has been addressed it has been found that the fundamental disease process is not dependent on exogenous stimuli but the severity of particular manifestations can be influenced . It has also been striking that multiple targeted genetic manipulations of normal mice including both traditional transgenes that lead to overexpression and site-directed transgenes that delete an active gene have been described as models of SLE . In these cases as well as in the spontaneous models the specificities 21-Deacetoxy Deflazacort of the autoantibodies can vary 21-Deacetoxy Deflazacort as well as the timing of disease onset the severity of the manifestations and the degree of clinical involvement particularly in the kidneys. Despite extensive investigations the failures in immunoregulation that underlie 21-Deacetoxy Deflazacort these genetic SLE models remain poorly understood . It is not known for sure which B cell tolerance checkpoints are breached in a given model and why. The autoantibody response to DNA Sm and other autoantigens resembles the normal response to exogenous antigens: it involves clonal expansion somatic mutation and a pattern of isotype use characteristic of a T-cell dependent immunization [8 9 Thus the cellular dynamics of the response may be basically normal. Yet the B-cell repertoire is abnormally autoreactive. This may be due to B cell intrinsic defects. In the case of some of the single gene models that target B-cell specific genes the B cell must be primarily involved. In some of the spontaneous multigenic models it can be shown that the genetic abnormalities must be present in the B cells for tolerance to be lost . In other cases however at least some of the 21-Deacetoxy Deflazacort genetic defects lie outside the B cells they are B-cell extrinsic . This applies to single gene models that target T cells antigen presenting cells or even enzymes or cell surface receptors that would influence the handling of autoantigens . Nevertheless each of these separate types of genetic defects results in a pattern of autoimmunity that mimics some important aspects of human SLE. 1.1 T cells and experimental SLE In this review we wish to focus more on the role of the T cell in SLE. As stated above the loss of B cell tolerance in SLE does appear in general to require the participation of T cells. Multiple T cells abnormalities have been described in human and in murine SLE although in most cases it is not clear if these are primary or secondary manifestations. Nevertheless it is striking how difficult it has been to demonstrate definitively the specificity of the T cells that provide help for autoantibody production . As an alternative approach to the study of the numerous genetic murine models for SLE a small number of experimental protocols have been found to produce a similar spectrum of autoantibodies. These include challenge with certain chemical agents such as heavy metals or pristane and the allogeneic interaction of T cells and B cells that are MHC diverse (Table 1). In all these cases normal mice are made to become autoimmune and their B cells lose tolerance to typical SLE autoantigens such as DNA and chromatin. We have been particularly interested in two chronic graft-versus-host disease (cGVHD) models over the last several decades (see Table 2). In.