Liposome encapsulated aurothiomalate reduces collagen-induced arthritis in DBA/1J mice.

Collagen-induced arthritis (CIA) generated in rats or mice has long been a model system for the study of rheumatoid arthritis in humans. In particular, this system has been used to study the mechanisms and effects of anti-arthritic drugs in the treatment of the disease. Sodium aurothiomalate (ATM) is an agent often used to treat rheumatoid arthritis in humans; however, it possesses inherent toxicities which limits its usefulness. Liposome-encapsulated drugs are currently being developed to minimize the toxicities associated with a variety of potentially beneficial drugs. We have chosen to encapsulate ATM into small unilamellar vesicles (SUVs) to determine whether greater efficacy would be achieved in treating CIA with SUV ATM as compared to using the free drug. SUVs were prepared from hydrogenated egg phosphatidylcholine and cholesterol. These SUVs were very stable. Vesicles stored at 4 degrees C lost only 0.09% of encapsulated ATM (SUV ATM) after 14 days and were able to reduce collagen-induced arthritis in these mice. Animals treated by i.m. injections of SUV ATM exhibited a 50% reduction in symptoms. More importantly, histological examination of knee joints of the affected animals verified that SUV ATM treatment prevented cellular infiltration of lymphocytes into the synovia of the collagen-sensitized mice. Conditioned media from spleen cell cultures was assayed for the presence of inflammatory lymphokines that might be affected by SUV ATM to account for the success in suppressing collagen-induced arthritis.

Permissive recognition during positive selection.

In the periphery alpha beta T lymphocytes recognize antigens in conjunction with major histocompatibility complex (MHC) molecules. In the thymus immature T cells are positively selected on MHC molecules in the apparent absence of cognate peptides. Thus, at different developmental stages a T cell responds to different epitopes, yet uses the identical alpha beta T cell antigen receptor (TcR). To explain this paradox it has been hypothesized that during positive selection immature T cells see peptides/ligands unique to the thymus, are selected by specific antagonists related to their cognate peptides, or are driven by lowered affinity thresholds of their TcR. Though different in detail, these theories rely on defined peptides uniquely matched to select certain TcR. However, we find that in a TcR-transgenic (TcR(trans +)) mouse severely limiting the diversity of peptides does not impair positive selection. We show that many unrelated peptides, including some naturally occurring on the cell surface, induce maturation of CD4-CD8+TcR(high) thymocytes. The same peptides when presented in conjunction with the selecting MHC molecule, are not recognized by peripheral T cells expressing the same TcR(trans). Therefore, these findings point to a promiscuous rather than discriminate recognition mode used by immature T cells.

How are alpha beta T cells positively selected in the thymus?

Thymus-derived (T) lymphocytes have the potential to express antigen receptors (TCR) that can recognize both self, as well as foreign antigens as they appear on the cell surface. In the thymus, positive selective allows the maturation of T cells that are able to see foreign antigens in conjunction with molecules encoded by genes of the major histocompatibility complex (MHC), whereas negative selection deletes auto-aggressive T cells. Control of T cell development is the only known function of the thymus. Therefore, it has been argued that recognition events responsible for selection of the T cell repertoire are guided by unique cellular interactions in the thymus. Here, we will show that positive selection can also occur on non-thymic cells. We will also argue that positive selection is not dependent on unique thymic accessory cells (AC) function. In other words, restricted recognition is not taught rather thymocytes learn it by themselves.

Thymic education--T cells do it for themselves.

The phenomenon of positive selection of developing T cells is well established. However, the cellular interactions that are responsible for selecting the restriction element are still ill defined. Here, Tomasz Pawlowski and Uwe Staerz discuss the latest developments in the field, as well as some new evidence suggesting that cells of epithelial or hematopoietic origin are not the only ones capable of selecting the restriction element for T cells expressing the alpha beta T-cell receptor.