Monday, December 24, 2007

2007 Flu vaccine: Pain, and gain?

The influenza vaccine contains three influenza virus strains – A (H1N1), A (H3N2), and B. The effectiveness of the vaccine depends on the match between the strains in the vaccine and those that are circulating in the community.

In years when vaccine and circulating strains were poorly matched, the vaccine can be ineffective (Bridges 2000). (Surprisingly, this study also concluded that even in a year when they were well matched, the cost outweighed benefit for people under 65.) In contrast, other studies have demonstrated some benefit even when the vaccine and circulating strains were not well matched. During the 2003-04 season, for example, vaccine effectiveness among people 50-64 years old was over 50% for protecting against contracting flu and 90% against hospitalization (Herrera 2006). The 2003-04 vaccine was similarly effective in children (Ritzwoller 2005). Children are responsible for the most transmission yet they are vaccinated at a lower rate than older adults.

For the current flu season, the Advisory Committee on Immunization Practices (ACIP) recommended vaccination with the strains A/Solomon Islands/3/2006 (H1N1)-like, A/Wisconsin/67/2005 (H3N2)-like, and B/Malaysia/2506/2004. The first detailed analysis of the current flu season was posted last week by the CDC. Between September 30 and December 1, 2007, World Health Organization and National Respiratory and Enteric Virus Surveillance System tested 24,897 respiratory specimens for influenza viruses; 559 (2.2%) were positive. Of these, 92% were influenza A viruses, and 8% were influenza B viruses. One hundred thirty-five of the influenza A viruses were subtyped; 83% of these were influenza A (H1) viruses, and 17% were influenza A (H3) viruses. CDC characterized 27 isolates to date (see table): 19 were influenza A (H1) isolates, 5 were influenza A (H3) isolates, and 3 were influenza B isolates. All 19 A/H1 viruses were Solomon Islands/3/2006-like. Two A/H3 isolates were Wisconsin/67/2005-like. Three A/H3 isolates were similar to Brisbane/10/2007, a strain recommended in the vaccines for the Southern Hemisphere. The three influenza B viruses characterized all belong to the Yamagata/16/88 lineage, whereas the Malaysia strain in the vaccine belongs to the Victoria lineage.

The fact that all H1 isolates are in the vaccine indicates that ACIP accurately predicted the rise of this strain. Although the efficacy of the vaccine is not established, its good match with the circulating strains suggests it will be beneficial. However, the H3 component matches only a minority of the circulating strains and the B component match none. Fortunately, these strains are less prevalent than the H1 strains.

Thursday, December 13, 2007

Reap before sowing: depleting host Hematopoetic Stem Cells improves transplantation

Hematopoetic stem cells (HSC) can generate all the cells of the blood, including the myeloid (erythrocytes, neutrophils, etc.) and lymphoid (B, T, and NK cells) lineages. HSC transplantation would be a valuable therapy for many conditions, including reconstitution of immune deficiencies and following radiation.

HSCs transplanted by intravenous injection efficiently home to the bone marrow. However, transplanted HSCs are only transiently productive, with donor cell frequencies in the blood reduced to < 1% within months, unless the host is “conditioned” by toxic regimens that are thought to work by depleting host HSC occupying a limiting number of niches in the bone marrow.

Here, Czechowicz and colleagues tested a targeted depletion with ACK2, an antibody that blocks the cytokine stem cell factor (SCF) receptor CD117 (c-kit). They report that ACK2 treatment of immunodeficient mice led to the transient removal of >98% of HSCs. (Using immunodeficient hosts avoided host-vs.-graft immune responses that would complicate the interpretation. Rag2-knockout mice lack mature B and T cell lineages due to failure to recombine V(D)J regions of immunoglobulin and T cell receptor genes. Common-gamma-chain-knockout mice are severely immunodeficient due to the failure to signal IL2, IL4, IL7, IL9, and IL15. ) Moreover, they show that donor HSC in ACK2-treated immunodeficient host mice produced up to 90% of the blood cells months after transplantation (figure 3a). This result demonstrates that host HSC must be depleted from a limiting number of niches to allow donor HSC to stably reconstitute an immunodeficent host.

Czechowicz et al. "Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches". Science. 2007 Nov 23;318(5854):1296-9.

Wednesday, December 5, 2007

T(H)-17 & Pathology

A colleague writes: "The recent group of papers in Nature Immunology (Stumhofer, Awasthi, and Fitzgerald) concerning TH-17 cells is driven, at least in part, by a question as old as the finding that some T cell lines or clones can cause a model inflammatory disease, EAE: What distinguishes pathogenic T cells in an EAE model from those cells that cannot cause inflammatory disease? With the emergence of the TH1-TH2 paradigm, it became “clear” that the pathogenic cells were of the proinflammatory, TH1 persuasion. This belief was then shaken by experiments using antibodies to, and knockouts of, to the p35 and p40 subunits of IL-12, which revealed that the “key cytokine” leading to pathogenicity was not the TH1-promoting IL-12 itself, but rather IL-23, which shares the p40 subunit. IL-23 was shown to promote a T cell population that produced TNF, IL-6, and IL-17, among other factors. Further study showed that differentiation of T cells toward this new “TH-17” phenotype was most effectively driven by IL-6 in combination with TGF-beta, whereas TGF-beta alone drove expression of Foxp3 and emergence of regulatory T cells.

This new group of papers incorporates a variety of approaches that all lead toward similar conclusions: TH-17s do not constitute a monolithic proinflammatory population, but can be influenced by either IL-27 or the combination of TGF-beta and IL-6 to include cells that secrete IL-10 in addition to IL-17 and that thus suppress inflammatory disease. As the figure from the paper by McGeachy et al. shows, IL-23 and the combination of TGF-beta and IL-6 both induce secretion of IL-17 by T cells during a recall response, but only the IL-23-treated cells cause EAE when transferred into naïve hosts. Other results in this paper and others show that this protection from disease is attributable to IL-10, which is secreted by T cells in response to IL-27 or the TGF-beta/IL-6 combination. These results may point the way to new modalities for steering otherwise harmful autoimmune responses into more benign channels."

McGeachy et al. "TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology." Nat Immunol. 2007 Dec;8(12):1390-7.