The GVH Reaction Is an Indication of Cell Mediated Cytotoxicity

The graft-versus-host (GVH) reaction develops when immu-nocomponent lymphocytes are injected into an allogeneic recipient whose immune system is compromised. Because the donor and recipient are not genetically identical, the grafted lymphocytes begin to attack the host, and the host's compromised state prevents an immune response against the graft. In humans, GVH reactions often develop after transplantation of bone marrow into patients who have had radiation exposure or who have leukemia, immunodeficiency diseases, or autoimmune anemias. The clinical manifestations of the GVH reaction include diarrhea, skin lesions, jaundice, spleen enlargement, and death. Epithelial cells of the skin and gastrointestinal tract often become necrotic, causing the skin and intestinal lining to be sloughed.

Experimentally, GVH reactions develop when immuno-competent lymphocytes are transferred into an allogeneic neonatal or x-irradiated animal. The recipients, especially neonatal ones, often exhibit weight loss. The grafted lymphocytes generally are carried to a number of organs, including

Strain X

4-5 days Spleen cells

Strain-Y cells

Strain X

4-5 days Spleen cells

Measure 51Cr release

FIGURE 14-17

LCM a

4-5 days Spleen cells

Lymphocytes

■ 51Cr-labeled strain-Y cells

4-5 days Spleen cells

J, Syngeneic

Lymphocytes i /W

51Cr-labeled cells infected with LCM virus

Measure 51Cr release

In vitro cell-mediated lympholysis (CML) assay. This assay can measure the activity of cytotoxic T lymphocytes (CTLs) against allogeneic cells (a) or virus-infected cells (b). In both cases the release of 51 Cr into the supernatant indicates the presence of CTLs that can lyse the target cells.

the spleen, where they begin to proliferate in response to the allogeneic MHC antigens of the host. This proliferation induces an influx of host cells and results in visible spleen enlargement, or splenomegaly. The intensity of a GVH reaction can be assessed by calculating the spleen index as follows:

Spleen index =

weight of experimental spleen/total body weight weight of control spleen/total body weight

A spleen index of 1.3 or greater is considered to be indicative of a positive GVH reaction. Spleen enlargement results from proliferation of both CD4+ and CD8+ T-cell populations. NK cells also have been shown to play a role in the GVH reaction, and these cells may contribute to some of the skin lesions and intestinal-wall damage observed.

SUMMARY

■ The cell-mediated branch of the immune system involves two types of antigen-specific effector cells: cytotoxic T lymphocytes (CTLs) and CD4+ T cells that mediate DTH reactions (discussed in Chapter 17). Compared with naive TH and TC cells, the effector cells are more easily activated, express higher levels of cell-adhesion molecules, exhibit different trafficking patterns, and produce both soluble and membrane effector molecules.

■ The first phase of the CTL-mediated immune response involves the activation and differentiation of TC cells, called CTL precursors (CTL-Ps).

■ Antigen-specific CD8+ populations can be identified and tracked by labeling with MHC tetramers.

■ The second phase of the CTL-mediated response involves several steps: TCR-MHC mediated recognition of target cells, formation of CTL/target-cell conjugates, reorientation of CTL cytoplasmic granules toward the target cell, granule release, formation of pores in the target-cell membrane, dissociation of CTL from the target, and the death of the target cell.

■ CTLs induce cell death via two mechanisms: the perforin-granzyme pathway and the Fas/FasL pathway.

■ Various nonspecific (non-MHC dependent) cytotoxic cells (NK cells, neutrophils, eosinophils, macrophages) can also kill target cells. Many of these cells bind to the Fc region of antibody on target cells and subsequently release lytic enzymes, perforin, or TNF, which damage the target-cell membrane, a process, called antibody-dependent cellmediated cytotoxicity (ADCC).

■ NK cells mediate lysis of tumor cells and virus-infected cells by perforin-induced pore formation, a mechanism similar to one of those employed by CTLs.

■ The expression of relatively high levels of class I MHC molecules on normal cells protects them against NK cell-mediated killing. NK cell killing is regulated by the balance between positive signals generated by the engagement of activating receptors (NKR-P1 and others) and negative signals from inhibitory receptors (CD94/NKG2 and the KIR family).

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