Week 4: Lecture 3

This lecture explores the quest for immune tolerance in transplant patients, aiming to eliminate the need for lifelong immunosuppression and its associated adverse effects.

# Introduction: Immunosuppression in Transplant Surgery

* Case Study: Richard Lee Norris received an extensive face transplant.

Requires lifelong immunosuppressant drugs* to prevent rejection.

Immune system can reactivate, leading to damaging rejection processes*.

# The Holy Grail: Engendering Immune Tolerance

* Goal: Achieve a state where the transplanted organ/tissue is recognized as self, allowing patients to be weaned off immunosuppressant drugs.

* Benefits of Immune Tolerance:

Patient's own immune system can protect against infection* and cancer.

Avoids severe adverse effects* of immunosuppressants (e.g., kidney damage, liver damage).

* Investigated Strategies to Induce Tolerance:

* Severe T cell depletion: Wiping out the recipient's immune system, followed by reconstitution (e.g., via bone marrow transplant) to see the donor tissue as self.

* Bone marrow chimerism: Introducing donor bone marrow to create a mixed (chimeric) immune system.

* Regulatory T cells: Utilizing these inhibitory T cell types.

* Lymphocyte Co-stimulation process interference: A major area of focus.

## Lymphocyte Co-stimulation Process & Intervention

* Normal T cell Activation:

1. An Antigen Presenting Cell (APC) presents an antigen to a T cell receptor.

2. An activated APC expresses the co-stimulatory molecule B7.

3. The T cell expresses CD28.

4. The engagement of B7 with CD28 provides a critical co-stimulatory signal.

5. This combined signaling leads to clonal proliferation of T cells.

6. Without the co-stimulatory signal, T cell activation does not occur.

* Natural Inhibition of T cells:

T cells also express CTLA-4* (Cytotoxic T-Lymphocyte-Associated protein 4).

When CTLA-4 binds to B7*, it inhibits T cell proliferation and actively inactivates the T cell.

* Pharmacological Interference (Blocking B7):

* Mechanism: Drugs are designed to block the B7 molecule on APCs, preventing its interaction with CD28 on T cells and thereby preventing T cell activation.

* Examples:

* Abatacept

* Belatacept

* Structure: These are fusion proteins consisting of an antibody FC region fused to the extracellular regions of the CTLA-4 molecule. They mimic CTLA-4 to bind B7.

* Efficacy of Belatacept:

A study published approximately eight years ago on kidney transplantation* showed Belatacept to be superior to cyclosporine.

Patients receiving Belatacept exhibited better kidney function* (measured by glomerular filtration rate) over time.

While an active immunosuppressant agent*, Belatacept unfortunately does not induce immune tolerance. The hunt for truly tolerogenic drugs continues.

# Emerging Areas: Xenotransplantation (Genetically Modified Pigs)

* Historical Context: Early attempts at animal-to-human transplantation (e.g., between animals and humans) failed due to immune rejection.

* Recent Progress: Significant interest and progress in genetically modifying pigs.

Pigs are modified to delete highly immune-activating antigens*.

* Application: Using organs, particularly hearts, from these modified pigs for human transplantation.

* First Surgery: Conducted a couple of years back; the patient survived for a limited period but was considered a success.

* Future Potential:

Offers a solution to the enormous waiting lists* for human organs.

Provides a more manageable and available supply of organs and tissues*.

Allows for planned and organized transplantation surgeries*.

Aims to overcome the limited resource of organs* that currently exists.

# Conclusion & Learning Outcomes

* Current Limitations of Immunosuppressant Therapy: Lifelong usage, significant adverse effects, and lack of true immune tolerance.

* Approaches for Immune Tolerance: Understanding and interfering with mechanisms like T cell depletion, bone marrow chimerism, regulatory T cell modulation, and co-stimulation blockade are key.

* Benefits of Tolerance for Patients: Improved quality of life, reduced risk of secondary diseases, and protection from opportunistic infections/cancers.

* Further Readings: Recommended textbook Abbas Atl for immunology, plus other articles.

* Cross-Lecture Relevance: Co-stimulation interference will be further discussed in immune stimulation and cancer lectures.