Appendix L. 
355 
Molecular understanding of the cellular immune response has led 
to new strategies to induce a state of permanent tolerance after 
transplantation. Several approaches have shown promise, including 
the use of tolerizing doses of class I HLA-molecules in various forms 
for the induction of specific unresponsiveness to alloantigens, and 
the use of synthetic peptides corresponding to HLA class II 
sequences. Other approaches include alteration in the balance of 
cytokines that direct the immune response away from the THl type 
of inflammatory response and graft rejection to the TH2 type of 
response that might lead to improved graft survival, and the use of 
agents to induce "co-stimulatory blockade" of T cell activation. This 
latter approach is based on the concept that blockade of a "second 
signal" to the T cell enables the signal provided to the T cell receptor 
by the HLA-peptide complex to induce antigen specific tolerance. 
The experimental use of human dendritic cells as tolerogenic 
agents has been limited due to the low frequency of circulating 
dendritic cells in peripheral human blood, the limited accessibility to 
human lymphoid organs, and the terminal state of differentiation of 
circulating human dendritic cells making their further expansion ex 
vivo difficult. Dendritic cells are migratory cells of sparse, but 
widespread, distribution in both lymphoid and non-lymphoid tissues. 
Although the earliest precursors are ultimately of bone marrow 
origin, the precise lineage of dendritic cells is controversial and 
includes both myeloid-derived and lymphoid-derived populations. 
Recent work has revealed that an expanded population of mature 
human dendritic cells can be derived from non-prohferating 
precursors in vitro is by culturing bone-marrow derived cells with a 
combination of cytokines. This method of enrichment for human 
dendritic cells from a precursor population can result in the 
production of dendritic cells that are tolerogenic to foreign antigens. 
Whether such cells could be useful when co-administered with an 
allograft transplant remains to be determined. Nevertheless, it is 
clear that considerable progress has been made in the past few years 
using approaches to manipulate the immune response to enable 
routine donor-specific tolerance, and there is reason to be optimistic 
that with better understanding of molecular and cellular mechanisms 
this goal could be attained. 
3. IMMUNOSUPPRESSIVE AGENTS COMMONLY USED IN 
ORGAN TRANSPLANT RECIPIENTS: BENEFITS AND ADVERSE 
OUTCOMES 
Cyclosporine 
PRE -PUBLICATION VERSION 
