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Chapter 27 : Transplantation Immunology

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Transplantation Immunology, Page 1 of 2

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Abstract:

This chapter provides definitions and key concepts of different types of transplantation. It discusses the roles of major histocompatibility complex and minor histocompatibility loci in graft acceptance and rejection. It talks about mechanisms of antigen recognition during graft rejection, immune effector mechanisms mediating rejection, immunological tolerance in graft acceptance and immune suppression for the prevention of rejection. Early experiments in transplantation were the experimental basis for identifying the MHC antigens. The key conclusions were based on the observations that it was possible to transplant tissues from one site to another on the same individual (autograft) whereas tissue transplanted from one individual to another (allograft) was inevitably destroyed or rejected by the recipient. The first major tissue typing system was the definition of the ABO blood group antigens by Karl Landsteiner in 1930. Mycophenolate mofetil is one of the new generation of synthetic drugs designed especially for use in transplantation. The major side effects of mycophenolate mofetil are gastrointestinal toxicity, especially dose-dependent diarrhea, esophagitis, and gastritis. Sirolimus interferes with late T-cell function and is classified as a target of rapamycin inhibitor. With greater understanding of the immune mechanisms that effect transplant rejection, better modalities of treatment can be developed with fewer side effects.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27

Key Concept Ranking

Major Histocompatibility Complex
0.51013917
Transforming Growth Factor beta
0.42377868
Immune Systems
0.4044609
0.51013917
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Figures

Image of Figure 27.1
Figure 27.1

The time frame of graft acceptance and graft rejection. When a graft is accepted (left column), plasmin activation, a normal part of the wound healing process, results in low levels of complement (Cʹ) activation. Relatively small numbers of white blood cells (WBC) are drawn to the site of engraftment by complement anaphylatoxins C3a, C5a, and C4a and assist the wound healing process. When a graft is rejected in a nonsensitized recipient (called a “first-set rejection”; middle column), small numbers of leukocytes are drawn to the site of engraftment by complement anaphylatoxins, but these lymphocytes recognize the graft as nonself tissue. T cells react to the foreign MHC antigens and produce cytokines that draw other immune cell types to the site. B cells can also be induced to produce antibodies (Ab) specific for donor antigens. These antibodies may contribute to graft destruction by triggering classical pathway complement activation as well as mediating antibody-dependent cell-mediated cytotoxicity (ADCC). The resultant activated macrophages and neutrophils produce reactive oxygen intermediates (ROIs), which further damage the engrafted tissue. Together, these immune mechanisms bring about the destruction of the donor tissue in about 2 weeks. If this same recipient receives a subsequent graft from the same donor or a donor whose tissues express MHC antigens substantially the same as those on the first donated organ, a similar graft rejection process (called a “second- set rejection”; right column) occurs, but the rejection happens much more quickly due to the presence of memory lymphocytes specific for donor antigens.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.2
Figure 27.2

The antigen specificity of a secondary or second-set rejection can be demonstrated experimentally. Two consecutive skin grafts from a strain X donor onto a strain Y recipient result in a secondary rejection. If the second graft is taken from a donor that is genetically different from the first donor, the second rejection has primary rejection kinetics.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.3
Figure 27.3

A summary of the immune effector mechanisms that can bring about graft rejection. Humoral mechanisms are shown on the left; cell-mediated mechanisms are on the right.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.4
Figure 27.4

Hyperacute rejection occurs if the recipient has preexisting antibodies specific for donor antigens. In earlier days, this was most commonly caused by incompatibility of the ABO blood-group antigens between the donor and recipient (this has been averted by routine screening of ABO antigens before transplantation). ABO antigens are expressed on vascular endothelial cells and will be quickly bound by recipient antibodies, resulting in complement activation, membrane attack complex (MAC) formation, and the generation of complement anaphylatoxins that draw leukocytes such as neutrophils to the site. The clotting system is activated, and blood clots form and block off the blood supply to the engrafted tissue. Rejection can be so fast that the graft never becomes completely revascularized.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.5
Figure 27.5

Graft acceptance is most successful when there are few genetic mismatches between the donor and recipient at the MHC locus. Redrawn from T. Moen et al., 850–854, 1980, with permission.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.6
Figure 27.6

Donor and recipient lymphocytes can be screened for MHC alleles by the use of allele-specific monoclonal antibodies. If lymphocytes are isolated and mixed with MHC-specific antibodies and complement, the antibodies can recognize the cognate MHC allotype and trigger complement activation and MAC formation. The MAC-permeabilized cells can be identified microscopically by their inability to exclude the dye trypan blue from their cytoplasm. A sample tissue typing carried out a small panel of MHC allele-specific antibodies. Note that in this simplified example, only one MHC I and one MHC II protein are shown, and each cell is assumed to be homozygous for the alleles encoding these MHC proteins.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.7
Figure 27.7

Direct versus indirect allorecognition. In indirect allorecognition, donor antigens (which may be donor MHC or any other donor protein that differs from recipient proteins) are proteolytically processed and presented to the recipient's T cells by the recipient's own (self) MHC. Direct allorecognition is the binding of recipient TCRs to intact allo-MHC on the surface of cells APCs of donor origin. These TCRs are binding directly to the foreign MHC without the need for processing of the foreign MHC.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.8
Figure 27.8

Possible sequence of events during graft rejection. () The transplant is performed. () Donor dendritic cells or macrophages present within the graft () leave the graft and stimulate recipient T cells by direct allorecognition. () Recipient T cells activated in this way recirculate throughout the recipient and enter the graft, where they kill donor cells in the graft. () Donor cells killed in this way release donor antigens, which can be phagocytosed by recipient APCs and presented to recipient T-cells on MHC II in a manner that is restricted by the recipient's self MHC (indirect allorecognition).

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.9
Figure 27.9

The experiments of C. G. Fathman and coworkers demonstrate the central role of CD4 T cells in graft rejection. Wild-type BALB/c mice reject skin grafts from allogeneic C57BL/6 mice. BALB/c mice with homozygous disruption of the gene encoding CD4 no longer reject the grafts. Rejection of the allogeneic skin grafts by CD4-knockout mice can be restored if the CD4-knockout mice are reconstituted with CD4 lymphocytes from wild-type BALB/c mice before the skin graft is carried out.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.10
Figure 27.10

Bone marrow transplantation. Mouse before experimental transplant. The mouse's own hematopoietic system is ablated by radiation, followed by transplant of heterologous marrow. The thymus becomes colonized with interdigitating dendritic cells (IDCs) of donor origin. The donor MHC molecules on these IDCs are the basis of negative selection of new thymocytes maturing in the thymus. New T cells that are selected on these donor MHC proteins will regard the recipient's MHC proteins as nonself and attack the recipient's tissues (a phenomenon called GVHD). (C) If the recipient is irradiated and then reconstituted with a mixture of donor and recipient marrow, the thymus will be colonized by IDCs of both donor and recipient origin, and new T cells will be educated to regard both donor and recipient MHC as self. Tolerance may also be maintained by a small population of regulatory T cells such as TH3 or Tr1 cells.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.11
Figure 27.11

Microchimerism. After a solid-organ transplant, small numbers of donor-derived leukocytes can be established throughout the body of the graft recipient. These donor cells persist for years and may aid in the establishment of central tolerance and in the maintenance of peripheral tolerance.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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Image of Figure 27.12
Figure 27.12

A simplified diagram of the central molecular events necessary for T-cell activation, highlighting the steps that are interrupted by various immunosuppressive drugs. Cyclosporine and tacrolimus complex with an immunophilin protein, and this complex prevents the dephosphorylation and activation of the transcription factor NF-AT. Corticosteroids inhibit the transcription of numerous cytokine genes, including the IL-2 gene, and reduce the stability of cytokine mRNAs. IL-2 action can also be inhibited through the use of IL-2 receptor (IL-2R)-specific monoclonal antibodies. Sirolimus (rapamycin) complexes with an immunophilin, and this complex inhibits the activity of proteins that regulate the entry of cells into the celldivision cycle. Azathioprine and mycophenolate mofetil prevent DNA synthesis by inhibiting purine biosynthesis.

Citation: Chandraker A, Sayegh M. 2004. Transplantation Immunology, p 649-666. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch27
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References

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1. Fox-Marsh, A.,, and L. C. Harrison. 2002. Emerging evidence that molecules expressed by mammalian tissue grafts are recognized by the innate immune system. J. Leukoc Biol. 71:401409.
2. Hall, B. M. 2000. Mechanisms of induction of tolerance to organ allografts. Crit. Rev. Immunol. 20:267324.
3. Le Moine, A.,, M. Goldman,, and D. Abramowicz. 2002. Multiple pathways to allograft rejection. Transplantation 73:13731381.
4. Li, X. C.,, T. B. Strom,, L. A. Turka,, and A. D. Wells. 2001. T-cell death and transplantation tolerance. Immunity 14:407416.
5. Martelli, M. F.,, F. Aversa,, E. Bachar-Lustig,, A. Velardi,, S. Reich- Zelicher,, A. Tabilio,, H. Gur,, and Y. Reisner. 2002. Transplants across human leukocyte antigen barriers. Semin. Hematol. 39:4856.
6. Pascual, M.,, T. Theruvath,, T. Kawai,, N. Tolkoff-Rubin,, and A. B. Cosimi. 2002. Strategies to improve long-term outcomes after renal transplantation. N. Engl. J. Med. 346:580590.
7. Rotrosen, D.,, J. B. Matthews,, and J. A. Bluestone. 2002. The immune tolerance network: a new paradigm for developing tolerance- inducing therapies. J. Allergy Clin. Immunol. 110:1723.
8. Teshima, T.,, and J. L. Ferrara. 2002. Understanding the alloresponse: new approaches to graft-versus-host disease prevention. Semin. Hematol. 39:1522.
9. Womer, K. L.,, M. K. Nadim,, and M. H. Sayegh. 2000. T-cell recognition of allograft target antigens. Curr. Opin. Organ Transplant. 5:2328.
10. Yamada, A.,, and M. H. Sayegh. 2002. The CD154-CD40 costimulatory pathway in transplantation. Transplantation. 73:S36S39.

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