Biomedical subjects

Thomas J Lang

Publications and source records attributed to Thomas J Lang.

4 recordsLinked to original sources

PubMed2007

Apoptotic splenocytes drive the autoimmune response to poly(ADP-ribose) polymerase 1 in a murine model of lupus.

Although defects in apoptosis have been linked to both human and murine lupus, the exact mechanisms remain unknown. Moreover, it is not clear whether such defects are primary or secondary events in disease pathogenesis. To address these issues, we used an induced model of murine lupus, the parent-into-F(1) model of chronic graft-versus-host disease (cGVHD) in which a lupus-like phenotype highly similar to human systemic lupus erythematosus is reliably induced in normal F(1) mice. We addressed the role of nuclear Ags modified by caspases during apoptosis as potential targets of the autoantibody response and our results identify poly(ADP-ribose) polymerase 1 (PARP-1) as a frequently targeted autoantigen. Additional proteins cleaved during apoptosis were also targeted by the immune response. Importantly, female mice exhibited significantly greater numbers of apoptotic cells in germinal centers and higher serum anti-PARP-1 Ab levels compared with male cGVHD mice. Serum anti-PARP-1 levels in male cGVHD mice could be elevated to levels comparable to those of female cGVHD mice by the injection of apoptotic syngeneic F(1) splenocytes early in the disease course. These results provide a mechanism by which lupus autoantibodies target apoptotic molecules. Specifically, T cell-driven polyclonal B cell activation characteristic of systemic lupus erythematosus is sufficient to saturate otherwise normal apoptotic clearance mechanisms, permitting apoptotic material to accumulate, serve as autoantigens, and drive autoantibody production.

Animals↗

PubMed2004

Estrogen as an immunomodulator.

Estrogen's role in the sex differences observed in autoimmune diseases such as systemic lupus, multiple sclerosis, and rheumatoid arthritis have remained unclear. Complicating the understanding of the immunomodulatory effects of estrogen are (1) the effects of estrogen on multiple components of the immune response; (2) its varied effects on different systems in which it appears pro-autoimmune, as in murine lupus, or anti-inflammatory, as in EAE; and (3) its effects on other hormones which are potentially immunomodulatory. Recent reports have shed light on the role of estrogen in the modulation of lymphocyte survival and expansion and in the elaboration of Th1 versus Th2 cytokines and on the mechanisms by which estrogen can activate via multiple signaling and genomic pathways in immune cells.

Animals↗

PubMed2003

Increased severity of murine lupus in female mice is due to enhanced expansion of pathogenic T cells.

A strong female predominance is a well-recognized feature of human lupus. The mechanism by which sex influences disease expression and severity is not fully understood. To address this question, we used the parent-into-F(1) (p-->F(1)) model of chronic graft-vs-host disease (cGVHD) in which lupus-like humoral autoimmunity and renal disease are induced in normal F(1) mice. An advantage of this model is that the pathogenic T cells driving disease (donor strain) can be studied separately from nonspecifically activated T cells (host strain). We observed that lupus-like disease using female donor and host mice (f-->F cGVHD) is characterized by more severe long-term disease (glomerulonephritis) than with male donor and host (m-->M cGVHD). Interestingly, differences in disease parameters could be seen at 2 wk after parental cell transfer, as evidenced by a 2- to 3-fold greater engraftment of donor CD4(+) T cells in f-->F cGVHD mice, which persisted throughout disease course. Enhanced engraftment of donor CD4(+) T cells in f-->F cGVHD mice was not due to differences in splenic homing, alloreactive precursor frequency, initial proliferation rates, or apoptotic rates, but rather to sustained high proliferation rates during wk 2 of disease compared with m-->M cGVHD mice. Crossover studies (m-->F, f-->M) demonstrated that enhanced donor CD4(+) T cell proliferation and engraftment segregate with the sex of the host. These results demonstrate that the sex of the recipient can influence the expansion of pathogenic T cells, thus increasing long-term the burden of autoreactive T cells and resulting in greater disease severity.

Animals↗

PubMed2002

In vivo CD86 blockade inhibits CD4+ T cell activation, whereas CD80 blockade potentiates CD8+ T cell activation and CTL effector function.

To address whether a functional dichotomy exists between CD80 and CD86 in naive T cell activation in vivo, we administered anti-CD80 or CD86 blocking mAb alone or in combination to mice with parent-into-F(1) graft-vs-host disease (GVHD). In this model, the injection of naive parental T cells into unirradiated F(1) mice results in either a Th1 cytokine-driven, cell-mediated immune response (acute GVHD) or a Th2 cytokine-driven, Ab-mediated response (chronic GVHD) in the same F(1) recipient. Combined CD80/CD86 blockade beginning at the time of donor cell transfer mimicked previous results seen with CTLA4Ig and completely abrogated either acute or chronic GVHD by preventing the activation and maturation of donor CD4(+) T cells as measured by a block in acquisition of memory marker phenotype and cytokine production. Similar results were seen with selective CD86 blockade; however, the degree of CD4 inhibition was always less than that seen with combined CD80/CD86 blockade. A more striking effect was seen with selective CD80 blockade in that chronic GVHD was converted to acute GVHD. This effect was associated with the induction of Th1 cytokine production, donor CD8(+) T cell activation, and development of antihost CTL. The similarity of this effect to that reported for selective CTLA4 blockade suggests that CD80 is a critical ligand for CTLA4 in mediating the down-regulation of Th1 responses and CD8(+) T cell activation. In contrast, CD86 is critical for the activation of naive CD4(+) T cells in either a Th1 or a Th2 cytokine-mediated response.

Acute Disease↗