Immunology: T Cell Activation and Anti-Rejection Drugs

Transplantation Immunology

• Lecture 3 covered allograft rejection and anti-rejection strategies.
• Aims of the lecture included promoting awareness of anti-rejection therapies and understanding mechanisms of action of different anti-rejection drug classes.
• By the end of the session, students should have knowledge of various immunosuppressive drugs used in preventing graft rejection and understand effects of classical inhibitors on T cells.

Overview of Acute Rejection

• Organ transplantation triggers DAMP release causing an inflammatory environment. Cytokines are released, cells get activated, and HLA expression increases.
• Donor dendritic cells (DCs) migrate to lymph nodes.
• Alloreactive T helper (T_H) cells recognize donor HLA on antigen-presenting dendritic cells (APCs). These T cells proliferate (clonal expansion).
• Alloreactive T_H cells then migrate to the graft. They are primed and activated, which triggers the release of cytokines. These cytokines drive rejection.
• Antibody-producing B cells are primed, resulting in anti-HLA antibodies targeting donor cells. This process involves antibody-dependent cellular cytotoxicity (ADCC).
• Ag-primed cytotoxic T lymphocytes (CTLs) destroy donor cells. CTLs target cells with HLA class I antigens. These often include endothelial cells and parenchymal cells

Prevention of Allograft Rejection - Introduction

• All vascularized allografts usually initiate an immune response against the graft.
• One or two HLA mismatches are sufficient to trigger rejection.
• Acute rejection starts within days of the transplant.
• Transplant recipients often require lifelong anti-rejection drugs to prevent chronic rejection

Prevention of Allograft Rejection - Anti-rejection Drugs

• Several classes of anti-rejection drugs exist, each with their unique mechanisms of action.
• Patients usually receive a combination of 2-3 anti-rejection drugs:
  • Induction therapy: Used immediately after transplant to induce high immunosuppression.
  • Maintenance therapy: A longer-term treatment.
• Anti-microbials are frequently required.

Anti-rejection Therapy - Rationale

• Anti-rejection drugs work by suppressing the immune system
• They target various aspects of immune cell function ranging from broad immunosuppression to selective targeting of signaling pathways involved in T-cell activation.

Activation of T Cells - General

• T cells need multiple signals for full activation.
• Activation is triggered by three main transcription factors: NFAT, NF-κB, and AP-1.
• The nature of the T cell response depends on the signals received:
  • Signal 1: TCR binding to MHC-peptide complex.
  • Signal 2: Accessory membrane molecules (e.g., CD28).
  • Signal 3: Cytokine signals (e.g., IL-2).

The Immunological Synapse

• The diagram shows that the interaction between the T cell and the APCs generates signals that activate the T cell.
• TCR:CD3 signaling activates calcineurin and induces NFAT for T cell activation.
• CD28 signaling triggers PI3K and mTOR activation leading to activation of AP-1 and NF-κB.
• These signals coordinate for IL-2 production and T cell activation

Anti-inflammatory Agents - Corticosteroids

• Corticosteroids are lipophilic and bind to intracellular receptors.
• The receptor-steroid complex binds to DNA sequences (CREs), which results in:
  • Production of lipomodulin; a phospholipase A2 inhibitor, decreasing arachidonic acid metabolism.
  • Inhibiting cytokine gene expression, leading to immunosuppression.

Anti-Rejection Therapies - Antimetabolites

• Purine analogues: Azathioprine (AZA), a derivative of 6-mercaptopurine (6-MP).
• They block purine biosynthesis (an important process for DNA synthesis), mostly effective for primary response to renal grafts, and lowers steroid dosages.

Classical Anti-rejection Drugs - Antimetabolites

• Mycophenolate mofetil (MMF) blocks inosine monophosphate dehydrogenase, an enzyme essential to guanine synthesis.
• Its effectiveness is most prominent in acute rejection within 6 months post-transplant.
• An alternative to azathioprine if the patient doesn't tolerate it well.

Classical Anti-Rejection Drugs - Calcineurin Inhibitors

• Calcineurin inhibitors (Cnls) inhibit calcineurin-dependent intracellular pathways, primarily in T cells.
• They down regulate cytokine gene transcription particularly IL-2 and its receptor IL-2R.
• They substantially reduce IL-2-induced T cell activation and maturation.
• Examples: Cyclosporin A (CSA), FK 506 (tacrolimus).

Classical Anti-Rejection Drugs - mTOR Inhibitors

• mTOR inhibitors (e.g., rapamycin/sirolimus, everolimus) bind to intracellular FKBP12.
• Rapamycin/sirolimus/everolimus bind with intracellular FKBP12 to prevent activation of mTOR.
• mTOR activity is reduced as a result, leading to reduced T-cell proliferation.
• They have less nephrotoxicity than calcineurin inhibitors (Cnls).

Selective Inhibition of Signaling Pathways in T Cells

• The diagram illustrates how these drugs impact T cells.
• Some drugs alter pathways related to calcineurin. others to mTOR, some to CD28.
• The graph and diagrams display how these inhibitors affect T cell pathways in detail.

Antibody-based (Specific) Anti-rejection Therapies

• Antibodies are used as induction therapy.
• Antilymphocyte globulin (ALG) and anti-thymocyte globulin (ATG) are commonly used.
• Reducing lymphocyte and T-cell activity.
• Anti-CD3, anti-CD25 (IL-2Rα), and anti-CD20 antibodies are used to target specific cells.

Co-stimulation Blockade of T Cells

• Belatacept is a recently introduced anti-rejection drug.
• It is an immunoglobulin G (Ig) fused to CTLA-4 (CD152).
• Belatacept binds to CD80/86 on antigen-presenting cells (APCs) preventing the binding of CD28 and significantly reduced T-cell activity.

Summary

• Suppressing alloreactive T-cells is needed due to rejection in most cases of allografts.
• Cytotoxic drugs are broad spectrum immune suppressants, but also exceptionally harmful to patients.
• Calcineurin inhibitors (CNI) and mTOR inhibitors are more selective therapies to inhibit T-cell activation.
• Combining CNIs and mTor inhibitors are used across varied phases of transplantation (induction and maintenance).
• mTOR inhibitors have notably less kidney toxicity than calcineurin inhibitors.

This quiz covers key concepts related to T cell activation signals, transcription factors, and the mechanisms of action of various anti-rejection drugs. It also addresses the immune response in transplant scenarios, including the timeframe for acute rejection and the rationale for using multiple immunosuppressive agents. Test your knowledge and understanding of these critical immunological principles.