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Monitoring Stem Cell Research 
Following binding of foreign proteins, class II HLA on antigen- 
presenting cells activate CD4-f T cells, which in turn activate 
cytotoxic CD8+ T cells to recognize the same foreign antigen bound 
to HLA class I (HLA-A, HLA-B, and HLA-C, molecules found on the 
surface of all cells) and destroy the target. The actual recognition of 
foreign HLA transplantation antigens by T cells is referred to as 
allorecognition. Two distinct pathways of allorecognition have been 
described, direct and indirect. The direct pathway involves receptors 
on the host T cells that directly recognize intact HLA antigens on the 
cells of the transplanted organ. The indirect pathway requires an 
antigen-presenting cell that internalizes the foreign antigen and 
presents it via its ov\m HLA class II molecule on the surface of an 
antigen-presenting cell to the CD4-1- helper T cells. 
Once recognition has taken place, an important cascade of events 
is initiated at the cellular level, culminating in intracellular release of 
ionized calcium from intracellular stores. The calcium binds with a 
regulatory protein called calmodulin, forming a complex that 
activates various phosphatases, particularly calcineurin. Calcineurin 
dephosphorylates an important cytoplasmic protein called nuclear 
factor of activated T cells (NFAT), resulting in its migration to the 
nucleus and induction of the production of various cytokines such as 
IL-2. These cytokines recruit other T cells to destroy the transplanted 
organ, ultimately resulting in rejection and loss of the graft. 
Immunosuppressive regimens used to prevent allograft rejection 
are aimed at inhibiting the various arms of the immune response, 
typically require multiagent combinations, and need to be 
maintained for the duration of life. The currently used 
armamentarium confers significant side-effect risks, including 
infectious and neoplastic complications. Moreover, despite success 
at preventing early allograft rejection, long-term survival of 
transplanted organs remains difficult to achieve and novel methods 
to achieve long-term tolerance are being actively sought. 
Stem cells obtained from embryonic or adult sources differ from 
other somatic cells in that they express very low levels of HLA 
molecules on their cell surfaces. This endows these cell types with 
the theoretical potential to escape the standard mechanisms of 
immune rejection discussed above. However, under conditions that 
enable cellular differentiation in vitro and in vivo each of these stem 
cell populations acquires high level expression of HLA molecules, 
suggesting that their long-term survival following transplantation in 
vivo may be hmited by typical immune rejection phenomena. Recent 
experimental data, however, provide striking counterintuitive 
examples that stem cells from both embryonic and adult sources may 
evade the recipient's immune system and result in long-term 
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