The putative mechanism of the immunomodulating effect of HLA-DR shared allogeneic blood transfusions on the alloimmune response.

Pretransplant blood transfusions have shown to improve organ allograft survival. However, the immunologic mechanism leading to this beneficial effect in clinical transplantation is still not clear. The observation that blood transfusions sharing an HLA-DR antigen with the recipient are more effective than HLA mismatched transfusions has led to the hypothesis that CD4(+) regulatory T (Treg) cells that recognize a foreign peptide in the context of the shared HLA-DR molecule play an important role in down-regulation of the immune response toward the graft. Available experimental evidence supports this hypothesis. Furthermore, these CD4(+) Treg cells are able to modulate antigen-presenting cells, which in their turn will induce Treg cells. As long as clinical transplantation tolerance by blood transfusions is not a reality, further studies on the mechanisms of the beneficial effect of pretransplant allogeneic blood transfusions are needed to obtain an effective protocol for the induction of clinically relevant Treg cells.

Regulatory developmental neurotoxicity testing: a model study focussing on conventional neuropathology endpoints and other perspectives.

Our aim was to investigate a model of the morphologic approach proposed in guidelines for developmental neurotoxicity testing (DNT). Hereto, a limited DNT study [EPA Health Effects Test Guidelines OPPTS 870.6300, 1996a. Developmental Neurotoxicity Study "Public Draft", United States Environmental Protection Agency; Prevention, Pesticides and Toxic Substances (7101); EPA 712-C-96-239, June 1996. ] was carried out with different doses of methylazoxy methanol acetate (MAM), known to affect brain morphology and neuron numbers in the developing brain. After gross examination, the brains of F1-animals were further dissected along neuro-anatomical landmarks to ensure homology between tissues of different individuals. The (relative) weight of the brain (parts) was determined. One brain half (alternating left/right to avoid lateralization) was further used for microscopic slide reading and measurement of brain layer width (linear morphometry); the other was set aside for stereologic investigation in a later phase of the study. In the offspring, a clear reduction in brain size (gross macroscopy) and weight (MAM high- and top-dose groups) was observed on postnatal days (PN) 22 and 62, but this reduction was hard to pinpoint in the microscope as the changes primarily appeared quantitative in nature, rather than qualitative. Linear measurements of brain layer width appeared very sensitive and efficient. This first step of a project is presented and the perspectives of a further stereologic investigation are discussed.

Differential effect of pretransplant blood transfusions on immune effector and regulatory compartments in HLA-sensitized and nonsensitized recipients.

BACKGROUND: Blood transfusion (BT) may elicit both harmful and beneficial immune responses against a subsequent organ graft. Immune parameters of a single, non leukocyte-depleted BT were investigated in two groups: non-human leukocyte antigen (HLA)-sensitized recipients with a one-HLA-DR matched donor (protocolled BT [PBT]) and females with previous exposure to HLA alloantigens through pregnancy (donor-specific transfusion [DST]). METHODS: Thirty-five percent of DST recipients and 9.5% of PBT recipients developed HLA antibodies after BT.Phenotypic and functional analyses were performed in pre-BT, 2 weeks post-BT, and more than 10 weeks post-BT samples (PBT: n=10; DST: n=14). RESULT: The number of donor-reactive interferon-γ-producing memory T cells increased 2 weeks post-BT, but only in the DST group, increased frequencies persisted beyond 10 weeks (P0.004). In the DST recipients, the proportion of natural killer cells (CD3(-)CD56(+)) significantly increased after BT (P=0.01), whereas in PBT recipients, the proportion of regulatoryT cells (CD4(+)CD25(+)Foxp3(+)CD127 low) significantly increased at 2 weeks post-BT (P=0.039). Microarray analysis confirmed increased activity of genes involved in function of natural killer cells,Tcells, and Bcells in DSTrecipients and increased expression of immune regulatory genes (galectin-1, Foxo3a, and follistatin-like 3) in PBT recipients. Galectin-1 expression by quantitative polymerase chain reaction was significantly enhanced in peripheral blood cells after PBT (P0.05). CONCLUSION: Decreased immune effector mechanisms combined with an increased immune regulatory cell signature after HLA-DR-matched BT in nonsensitized patients is in line with clinical observations of improved outcome of a subsequent graft. Previous sensitization, however, may lead to HLA antibody formation and prolonged donor-specific memory T-cell reactivity after BT.