Monday, August 21, 2006

Transplantation: Manipulated dendritic cells are tolerogenic

drj writes, "Immune suppressive drugs enable clinical transplantation, the only therapy for end-stage organ failure, at the cost of reducing patient protection from infections. Ideally, a patient could be made specifically tolerant of a graft without blocking other immune responses. Using a mouse heart transplantation model, Ichim and colleagues suggest several procedures for doing just that, by manipulating certain costimulatory or antigen presenting skills of allogeneic (donor) dendritic cells (DC).

The authors first induced tolerance through means they have established earlier – treatment of recipient mice with blocking antibodies specific for CD45RB and with LF15-0195 (LF), an analogue of the antirejection drug 15-deoxyspergualin. DC recovered from the spleens of mice with long term surviving grafts stimulate allogeneic (donor) T cells to make interleukin (IL)-4 and IL-10 but not interferon-gamma. Next, they identified 4 treatments that produce similar results: (1) Gene transfer and expression of human Fas ligand (FasL) in DC generate “killer DC” that cause apoptosis of allogeneic T cells. (2) Treatment of DC with LF15-0195 blocked activation of the transcription factor NF-kappaB. (3) DC treated with (MHC) class (II) invariant chain peptide (CLIP). (4) Finally, DC treated with short, interfering RNA (siRNA) corresponding to IL-12 blocked its expression and reduced interferon-gamma while increasing IL-4 expression. Each treatment reduced the ability of DC to specifically stimulate allogeneic T cells, suggesting they could be used to establish transplant tolerance. Although the altered DC phenotype resembles those of DC in demonstrably tolerant mice, it will be necessary to test these treatment are able to induce transplant tolerance.
Ichim et al., Prevention of allograft rejection by in vitro generated tolerogenic dendritic cells. Transpl Immunol. 2003;11:295-306
(Originally posted on Dec. 10, 2003)

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