Biomedical Engineering Reference
In-Depth Information
after transplantation. During the early stages of World War II, Scottish plastic
surgeon Tom Gibson collaborated with British zoologist Peter Medawar to inves-
tigate why skin taken from one human being will not form a permanent graft on the
skin of another person. In 1943, Medawar and Gibson discovered that the rejection
of skin graft was mediated by an antigen-antibody reaction of the host immune
system (Gibson and Medawar, 1943). Medawar was eventually awarded the Nobel
Prize in Medicine & Physiology in 1960 for his continued research in transplant
immunology. The latter half of the 20th century saw a growing use of human
cadaveric allograft skin as a biological dressing in burn patients (Brown
et al
.,
1953), particularly after allograft skin was demonstrated to stimulate neo-vascu-
larization (O'Donaghue and Zarem, 1971). In 1955, Harrison reported the first
successful kidney transplant between identical twins (Harrison
et al
., 1956) and the
same transplant group reported a successful cadaveric renal transplant in 1963
(Merrill
et al
., 1963). Subsequent advances in immunologic typing of tissues and
immunosuppression have allowed solid organ allograft transplantation to achieve
long term graft function and widespread clinical practice. Research in transplant
immunology is now focusing on induction of tolerance in allogeneic and xenoge-
neic tissues in the absence of long-term immunosuppression.
5.4.2 Immunology of allogeneic transplantation
The rejection of allogeneic tissue transplants occurs via cellular and humoral
immunologic responses. These responses are generated when the host defense
system detects foreign antigens expressed on the donor cell surface. The antigen-
presenting molecules are termed major histocompatibility complex (MHC) antigens
or human leukocyte antigens (HLA) in humans. The HLAs provide a molecular
fingerprint based on six closely linked genes providing more than 100 serologi-
cally identifiable combinations (Auffray and Strominger, 1986). Each individual
has two MHC regions: a paternally and a maternally inherited collection of HLA
genes, or haplotype. HLA genes are divided into two classes: class I HLA genes
referred to as HLA-A, -B and -C, and class II genes referred to as HLA-DR, -DQ,
and -DP. In humans, class I antigens are expressed on all nucleated cells and
platelets, whereas class II antigens are only expressed on hematopoietic cells, such
as B lymphocytes, activated T lymphocytes, and monocytes and tissue fixed
antigen presenting cells (APCs), such as macrophages and dentritic cells. Match-
ing of HLA-A, -B, and -DR is the most important factor determining long term
renal allograft survival (Lee and Butler, 1997).
The process of allogeneic rejection begins with the presentation of a foreign
alloantigen on the surface of APCs in conjunction with class II MHC molecules.
Identification of this alloantigen pairing by immature T cells results in their
maturation and amplification. The dissemination of immunomodulatory cytokines,
including interleukin-1 and -2, results in sensitization and activation of T helper/
inducer, CD4+ cell subpopulations, and the clonal expansion of both cellular (T
