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Biomedical subjects

John Kappler

Publications and source records attributed to John Kappler.

27 records · Page 2Linked to original sources
PubMed2002

Liposomal clodronate as a novel agent for treating autoimmune hemolytic anemia in a mouse model.

Autoimmune hemolytic anemia (AIHA) is a disease in which autoantibodies against red blood cells (RBCs) lead to their premature destruction. Most clinically significant autoantibodies are of the immunoglobulin G (IgG) type, which leads primarily to the uptake and destruction of RBCs by splenic and hepatic macrophages. Therapies such as corticosteroids and splenectomy are directed at interfering with this process. Liposomally encapsulated clodronate (dichloromethylene diphosphonate) has previously been found to be a potent antimacrophage agent. It selectively depletes animals of macrophages within 24 hours of administration by inducing apoptosis in these cells. Therefore, we hypothesized that liposomal clodronate would be a useful agent for treating AIHA. We tested this hypothesis in a mouse model of AIHA in which animals were given either anti-RBC antibodies or preopsonized RBCs. In either case, liposomal clodronate substantially decreased RBC destruction. This drug formulation was effective within hours by first blocking and then depleting phagocytic macrophages, and its action lasted for 1 to 2 weeks. Thus, in AIHA, liposomal clodronate therapy may act like a temporary, medicinal splenectomy. As such, it may prove useful in situations where rapid response to therapy is critical or other medical therapies are inadequate.

Anemia, Hemolytic, Autoimmune↗
PubMed2002

CD25+CD4+ T cells contribute to the control of memory CD8+ T cells.

Previously we demonstrated that IL-15 and IL-2 control the number of memory CD8+ T cells in mice. IL-15 induces, and IL-2 suppresses the division of these cells. Here we show that CD25+CD4+ regulatory T cells play an important role in the IL-2-mediated control of memory phenotype CD8+ T cell number. In animals, the numbers of CD25+CD4+ T cells were inversely correlated with the numbers of memory phenotype CD8+ T cells with age. Treatment with anti-IL-2 caused CD25+CD4+ T cells to disappear and, concurrently, increased the numbers of memory phenotype CD8+ T cells. This increase in the numbers of CD8+ memory phenotype T cells was not manifest in animals lacking CD4+ cells. Importantly, adoptive transfer of CD25+CD4+ T cells significantly reduced division of memory phenotype CD8+ T cells. Thus, we conclude that CD25+CD4+ T cells are involved in the IL-2-mediated inhibition of memory CD8+ T cell division and that IL-2 controls memory phenotype CD8+ T cell numbers at least in part through maintenance of the CD25+CD4+ T cell population.

Animals↗
PubMed2002

Alternate interactions define the binding of peptides to the MHC molecule IA(b).

We have solved the crystal structure of the MHCII molecule, IA(b), containing an antigenic variant of the major IA(b)-binding peptide derived from the MHCII IEalpha chain. The four MHC pockets at p1, p4, p6, and p9 that usually bind peptide side chains are largely empty because of alanines in the peptide at these positions. The complex is nevertheless very stable, apparently because of unique alternate interactions between the IA(b) and peptide. In particular, there are multiple additional hydrogen bonds between the N-terminal end of the peptide and the IA(b) alpha chain and an extensive hydrogen bond network involving an asparagine at p7 position of the peptide and the IA(b) beta chain. By using knowledge of the shape and size of the traditional side chain binding pockets and the additional possible interactions, an IA(b) peptide-binding motif can be deduced that agrees well with the sequences of known IA(b)-binding peptides.

Amino Acid Motifs↗
PubMed2002

Structural basis of cytochrome c presentation by IE(k).

The COOH-terminal peptides of pigeon and moth cytochrome c, bound to mouse IE(k), are two of the most thoroughly studied T cell antigens. We have solved the crystal structures of the moth peptide and a weak agonist-antagonist variant of the pigeon peptide bound to IE(k). The moth peptide and all other peptides whose structures have been solved bound to IE(k), have a lysine filling the p9 pocket of IE(k). However, the pigeon peptide has an alanine at p9 shifting the lysine to p10. Rather than kinking to place the lysine in the anchor pocket, the pigeon peptide takes the extended course through the binding groove, which is characteristic of all other peptides bound to major histocompatibility complex (MHC) class II. Thus, unlike MHC class I, in which peptides often kink to place optimally anchoring side chains, MHC class II imposes an extended peptide conformation even at the cost of a highly conserved anchor residue. The substitution of Ser for Thr at p8 in the variant pigeon peptide induces no detectable surface change other than the loss of the side chain methyl group, despite the dramatic change in recognition by T cells. Finally, these structures can be used to interpret the many published mutational studies of these ligands and the T cell receptors that recognize them.

Amino Acid Motifs↗
PubMed2002

Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family ligands.

TALL-1/BAFF/BLyS was recently identified as a member of the tumor necrosis factor (TNF) ligand family. The crystal structure of the functional soluble TALL-1 (sTALL-1) has been determined at 3.0 A. sTALL-1 forms a virus-like assembly with 200 A diameter in the crystals, containing 60 sTALL-1 monomers. The cluster formation is mediated by a "flap" region of the sTALL-1 monomer. The virus-like assembly was also detected in solution using gel filtration and electron microscopy. Deletion of the flap region disrupted the formation of the virus-like assembly. The mutant sTALL-1 still bound its receptor but could not activate NF-kappaB and did not stimulate B lymphocyte proliferation. Finally, we found the virus-like cluster of sTALL-1 exists in physiological condition. We propose that this virus-like assembly of sTALL-1 is the functional unit for TALL-1 in vivo.

Amino Acid Sequence↗
PubMed2002

Molecular mechanisms of activated T cell death in vivo.

The culmination of the immune response involves the death of the majority of the activated antigen-specific T lymphocytes. The death of these cells is important to prevent autoimmunity, to decrease the metabolic cost to the organism and to ensure T cell homeostasis. This review will focus on the mechanisms that, in animals, control the death of these activated cells. At least two separate types of cell death can occur (activation-induced cell death and activated T cell autonomous death) via death receptors such as Fas or the Bcl-2 related protein Bim, respectively. Finally, adjuvants that enable T cell survival may operate via NF-kappaB and Bcl-3 rather than cytokines.

Animals↗
PubMed2002

Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim.

At the end of the T cell response, the majority of the activated T cells die. We activated Vbeta8(+) T cells with staphylococcal enterotoxin B (SEB) in vivo and monitored the expansion and deletion of Vbeta8(+) T cells. We found that, in response to SEB, activated T cells died in vivo in the absence of Fas or TNF-R signaling but not when they overexpressed human Bcl-2. We also found that Vbeta8(+) T cells from Bim-deficient mice are resistant to SEB-induced deletion. While Bim levels did not change, endogenous Bcl-2 levels within Vbeta8(+) T cells decrease following SEB injection. Thus, the death of superantigen-stimulated T cells in vivo is mediated by Bim and may be modulated by a decrease in Bcl-2.

Animals↗
PubMed2002

RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process.

An examination of differences in gene expression between memory and naive phenotype T cells revealed elevated levels of mRNA for several chemokines, especially RANTES, in memory phenotype T cells. Although RANTES mRNA is spliced and cytoplasmic, these cells do not contain or secrete significant amounts of RANTES protein without TCR stimulation. This secretion is independent of transcription, but requires translation. In vivo, CD8+ memory T cells proliferate continuously and slowly in response to IL-15; however, IL-15 does not stimulate RANTES secretion. These results show that memory phenotype CD8+ T cells use preexisting mRNA to produce and secrete RANTES rapidly following TCR stimulation. Such storage of preformed mRNAs for important inflammatory mediators may contribute to the speed of secondary immune responses.

Animals↗