Graft-versus-host disease (GVHD) remains the major complication after allogeneic bone marrow transplantation (BMT). The process whereby acute GVHD mediated by alloreactive donor T cells transitions into chronic GVHD, which is characterized by prominent features of auto-immunity, has long been unresolved. In this study, we demonstrate that GVHDassociated autoimmunity and, by extension, chronic GVHD is attributable to the progressive loss of CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells during the course of acute GVHD. This leads to the expansion of donor-derived CD4 ؉ T cells with T H 1 and T H 17 cytokine phenotypes that release proinflammatory cytokines and cause autoimmune-mediated pathological damage. These T cells are present early after transplantation, indicating that the pathophysiological events that lead to chronic GVHD are set in motion during the acute phase of GVHD. We conclude that the absence of CD4 ؉ CD25 ؉ regulatory T cells coupled with unregulated T H 1 and T H 17 cells leads to the development of autoimmunity and that donor-derived T H 1 and T H 17 cells serve as the nexus between acute and chronic GVHD. (Blood.

NF-B is a transcription factor that controls the expression of a number of genes important for mediating immune and inflammatory responses. In this study, we examined whether bortezomib and PS-1145, each of which inhibits NF-B, could protect mice from lethal graft-versus-host disease (GVHD), which is characterized by immune activation and proinflammatory cytokine production. When administered within the first 2 days after transplantation, bortezomib and PS-1145 both protected mice from fatal GVHD, did not compromise donor engraftment, and effected marked reduction in the levels of serum cytokines that are normally increased during GVHD. Extending the course of bortezomib administration or delaying the initiation of this agent for as few as 3 days after bone marrow transplantation (BMT), however, significantly exacerbated GVHD-dependent mortality because of severe pathological damage in the colon. In contrast, prolonged administration of PS-1145, which, unlike bortezomib, is a selective inhibitor of NF-B, caused no early toxicity and resulted in more complete protection than that observed with an abbreviated PS-1145 treatment schedule. These results confirm a critical role for NF-B in the pathophysiology of GVHD and indicate that targeted inhibition of NF-B may have a superior therapeutic index and may constitute a viable therapeutic approach to reduce GVHD severity. (Blood. 2006;107:827-834)

Lymphatic filariasis is caused by the parasitic nematodes Brugia malayi and Wuchereria bancrofti and asparaginyl-tRNA synthetase (AsnRS) is considered an excellent antifilarial target. The discovery of three new tirandamycins (TAMs), TAM E (1), F (2), and G (3), along with TAM A (4) and B (5), from Streptomyces sp. 17944 was reported. Remarkably, 5 selectively inhibits the B. malayi AsnRS and efficiently kills the adult B. malayi parasite, representing a new lead scaffold to discover and develop antifilarial drugs.

Lymphatic filariasis is caused by the Brugia malayi parasite. Three new congeners of the depsipeptide WS9326A (1), WS9326C (2), WS9326D (3) and WS9326E (4), were isolated from Streptomyces sp. 9078 by using a B. malayi asparaginyl-tRNA synthetase (BmAsnRS) inhibition assay. WS9326D specifically inhibits the BmAsnRS, kills the adult B. malayi parasite, and does not exhibit significant general cytotoxicity to human hepatic cells, representing a new lead scaffold for antifilarial drug discovery.