Cell-Mediated Immunity

Cell-mediated immune responses involve Th1-mediated activation of macrophages (type IV hypersensitivity) and generation of CD8⁺ cytotoxic T-lymphocytes (CTLs). Th1 cells secrete cytokines, which recruit and activate macrophages. Macrophages are capable of killing intracellular bacteria and produce a localized inflammatory response. This also occurs with chemicals such as urushiol from poison ivy (contact hypersensitivity).

CTLs mediate antigen-specific lysis of tumor cells, virally infected cells, and graft/transplant cells. Generation of CTLs for all three functions generally involves similar mechanisms (Fig. 6-3). Naïve, precursor CTLs (pCTLs) require activation by two signals, as described for Th cells. The first is delivered by binding of peptide antigens associated with MHC Class I molecules on APCs to the T-cell receptor on CD8⁺ pCTLs. The second is provided by receptor-ligand interaction of costimulatory molecules. Th1 cells produce cytokines that stimulate dendritic cells to up regulate a costimulatory molecule that will activate antigen-stimulated CD8⁺ cells. Activated CTLs produce IL-2, which stimulates its own proliferation and differentiation. In certain situations, APCs that contain high levels of costimulatory molecules are able to activate CD8⁺ CTLs without the help of Th1 cells. Antigen recognition and binding of activated CTLs to antigen on cells result in cell lysis.

FIGURE 6–3 Cytolytic T-lymphocyte (CTL) generation against tumor cells. CTLs may be generated with or without support from Th1 cells. Tumor antigens are taken up by APCs, processed, and presented with MHC class II molecules to CD4⁺ T-helper cells. This leads to the generation of effector Th1 cells. Activated Th1 cells stimulate the upregulation of costimulatory molecules (B7) on APC and provide the second signal to antigen-activated precursor CTLs (pCTL). Activated CTLs secrete IL-2 and stimulate their own proliferation and differentiation to effector CTLs. Tumor cells are then recognized and lysed by effector CTLs.

Humoral Immunity

Th2 cells secrete cytokines that stimulate proliferation and differentiation of B cells to antibody-secreting plasma cells or to long-lived memory cells (Fig. 6-4). Specific antibodies can remove harmful foreign antigens (e.g., bacterial toxins) by binding to and neutralizing their effects. Antigen-antibody immune complexes can activate complement to elicit a local inflammatory reaction for further antigen removal by phagocytes. Once bound to foreign protein or bacteria, the Fc region of antibodies can bind to receptors on phagocytic cells, leading to internalization of the invading pathogens.

FIGURE 6–4 Generation of a humoral immune response. APCs internalize antigen through phagocytosis or antibody-mediated endocytosis (B cells). The antigen is processed, and the resulting peptides are presented on the surface to naïve T cells in the setting of MHC class II molecules. The interaction of the specific TCR: peptide/MHC pair and the costimulatory molecules B7/CD28 is necessary for full activation. The activated T cell produces IL-2, which leads to its proliferation and upregulation of CD25, a component of the IL-2 receptor. CD40L is also up regulated. In the lymphoid organs such as the lymph nodes or the spleen, the activated T cell interacts with a B cell that is specific for the same antigen and provides help to the B cell through interaction of CD40L and CD40 and by producing cytokines such as IL-4 that lead to B cell activation and proliferation. The activated B cells can differentiate into antibody-producing plasma cells or into memory cells.

Glucocorticoids

The actions of the corticosteroids are discussed in Chapter 39. Glucocorticoids are effective in treating autoimmune diseases and preventing graft rejection because of their immunosuppressive and anti-inflammatory effects. When glucocorticoids are administered, the numbers of circulating lymphocytes, basophils, and eosinophils decrease over a 24-hour period, whereas the number of neutrophils increases. In addition, changes in glucocorticoid concentrations during the normal diurnal cycle and in stressful situations correlate with decreases in circulating lymphocytes. Lymphopenia is attributed to migration of cells into extravascular spaces, with more T cells than B cells or monocytes migrating. Most cells migrate to bone marrow. High-dose glucocorticoid therapy is also known to reduce the size of lymphoid organs.

Although glucocorticoid-induced lymphopenia is well documented, its importance in immunosuppression is unclear. It is known, however, that glucocorticoids alter the immune response by directly changing immune cell function, and the macrophage is a primary target. Exposure of macrophages to glucocorticoids results in decreased IL-1 production, decreased expression of MHC class II antigens, and decreased phagocytosis of virus-infected cells, tumor cells, bacteria, and fungi. T and B cells are also directly affected, with T-cell-mediated responses affected to a greater extent.

Antiproliferative/Antimetabolite Agents

This class of drugs acts predominantly by deleting proliferating cells. Proliferation is a key step in the immune response and therefore a primary target. Although many cytotoxic agents have been used in treating cancer, a relatively small number of drugs are used in treating immune diseases. The main categories are alkylating agents, such as cyclophosphamide, and antimetabolites, such as azathioprine and methotrexate.

The structure of cyclophosphamide, its activation to phosphoramide mustard and acrolein, and its antitumor actions are discussed in Chapter 54. The ways in which the active metabolites phosphoramide mustard and acrolein alter the immune response are unclear. The mustard is believed to alkylate DNA and mediate the antiproliferative and immunosuppressive effects. This is consistent with the hypothesis that selective cytotoxic effects on B cells are attributable to a greater proliferation rate. However, the highly reactive, sulfhydryl-binding acrolein may also play an important role in the drug’s action.

The structure of azathioprine is shown in Figure 6-5. This drug is metabolized to the antiproliferative drug 6-mercaptopurine (see Chapter 54), which is further metabolized to the active antitumor and immunosuppressive thioinosinic acid inhibiting hypoxanthine-guanine phosphoribosyltransferase, which catalyzes the conversion of purines to the corresponding phosphoribosyl-5′ phosphates and the conversion of hypoxanthine to inosinic acid. This leads to the inhibition of cellular proliferation. The immunosuppressive effects of azathioprine stem from its antiproliferative actions.

FIGURE 6–5 Structures of several immunosuppressants.

The immunosuppressive effects of mycophenolate mofetil are mediated by inhibiting T and B lymphocyte proliferation through inhibition of purine synthesis. Purine nucleotides are synthesized in most cell types by the de novo or salvage pathways. Mycophenolate mofetil selectively inhibits inosine monophosphate dehydrogenase, blocking de novo synthesis of purines. Lymphocytes, unlike other rapidly dividing cell types, depend entirely on the de novo pathway for purine synthesis, thus explaining the selectivity of this agent for lymphocytes. Mycophenolate mofetil is an antimetabolite like azathioprine and is reported to have greater selectivity for T and B lymphocytes than for neutrophils and platelets. It inhibits the generation of CTLs and antibody-producing cells by inhibiting the proliferation of T and B lymphocytes. It also affects expression of adhesion molecules on lymphocytes, thereby inhibiting their binding to vascular endothelial cells, which is necessary for migration from the circulation to tissues.

Methotrexate was originally developed as an anticancer drug (see Chapter 54) but is now being used widely at lower doses in several inflammatory diseases, including rheumatoid arthritis. The immunological and antitumor mechanisms are similar. An antimetabolite, methotrexate binds and inactivates dihydrofolate reductase, leading to inhibition of the synthesis of thymidylate, inosinic acid, and other purine metabolites. Methotrexate also stimulates the release of adenosine, which inhibits stimulated neutrophil function and has potent anti-inflammatory properties.

Calcineurin Inhibitors/Immunophilin Binding Agents

Calcineurin inhibitors down regulate immune responses by inhibiting the production of IL-2 in activated T cells. IL-2 is a key driver of many immune responses and especially important in mediating organ transplant rejection. The two calcineurin inhibitors cyclosporine and tacrolimus bind to cyclophilin and FK binding protein, respectively, and the drug-immunophilin complex binds to calcineurin. This leads to dephosphorylation of nuclear factor for activated T cells (NFAT) and prevention of its translocation to the nucleus, causing down regulation of cytokine transcription (Fig. 6-6).

FIGURE 6–6 Mechanism of action of cyclosporine and tacrolimus. Transcription of various cytokines requires the transcription factor NFAT. Removal of a phosphate group from NFAT by the Ca⁺⁺/calmodulin-dependent calcineurin phosphatase results in translocation of NFAT to the nucleus, where it binds to the NFAT binding element of the promoter region of cytokine genes (IL-2, IL- 3, IL-4, GM-CSF, TNF-α, IFN-γ). This results in activation of cytokine transcription. Cyclosporine and tacrolimus bind to cyclophilin and FKBP-12 (known as immunophilins), respectively. These complexes inhibit calcineurin activity and inhibit NFAT dephosphorylation.

Cyclosporine is a cyclic endecapeptide purified from fungi (see Fig. 6-5). It primarily affects T-cell–mediated responses, whereas most humoral immune responses not requiring T cells are spared. The effectiveness of cyclosporine stems from its selective inhibition of Th cell activation. Its major effect on Th cells is inhibition of cytokine production. Decreased IL-2 production in turn leads to a decrease in IL-2 receptors and in a lack of responsiveness of CTL precursor cells. Because there is positive feedback through IL-2 production and IL-2 receptors, the decreased IL-2 production of Th cells also leads to decreased IL-2 receptors. Cyclosporine does not, however, affect the proliferative response of activated CTLs to IL-2 or the lytic activity of CTLs. Consistent with this is the observation that cyclosporine is effective only during the very early stages of antigen activation of Th cells. There is also evidence for inhibition of macrophage antigen presentation and IL-1 production by macrophages.

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