Immunology: Graft Rejection and T Lymphocyte Maturation

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Questions and Answers

What is one of the immunologic advantages of using iPS cells derived from patients?

They produce more immunosuppressive cytokines.

They require MHC matching to prevent rejection.

They will not be rejected by the immune system. (correct)

They can be harvested from embryonic stem cells.

Which cytokines are produced by regulatory T cells to suppress immune responses?

IL-10 and TGF-β (correct)

IFN-γ and IL-4

IL-1 and TNF-α

IL-2 and IL-6

What genetic technology is being explored to modify allogeneic embryonic stem cells?

CRISPR-Cas9 genome editing technology (correct)

RNA interference techniques

Gene therapy using plasmids

Transcription factor modulation

What is a potential application for genetically modified pigs in medicine?

Facilitating human organ transplantation Signup and view all the answers

What is one of the mechanisms through which regulatory T cells suppress immune responses?

Reducing the stimulation capability of APCs Signup and view all the answers

What is the primary outcome of negative selection in T lymphocyte maturation?

Elimination of lymphocytes binding strongly to self-antigens Signup and view all the answers

Which of the following accurately describes MHC molecules?

MHC polymorphism allows for a diverse presentation of peptides. Signup and view all the answers

In which location of the human genome are MHC genes primarily found?

Short arm of chromosome 6 Signup and view all the answers

What happens when a graft from an (A × B) F1 animal is placed into a recipient from strain A or B?

The graft will be rejected by both parental strains. Signup and view all the answers

Which of the following pairs accurately represent the class II MHC gene loci?

HLA-DR, HLA-DQ, HLA-DP Signup and view all the answers

What is the term used to describe the set of MHC alleles present on each chromosome?

MHC haplotype Signup and view all the answers

What is the reason behind T cell activation through indirect alloantigen recognition?

Presentation of processed alloantigens by recipient APCs Signup and view all the answers

Which process involves the failure to be positively selected by self MHC molecules?

Negative selection Signup and view all the answers

What is the primary outcome of glucocorticoid receptor activation in relation to histone acetylation?

Increased suppression of activated inflammatory genes Signup and view all the answers

What role does HSC transplantation play in treating hematopoietic diseases?

It involves the replacement of destroyed hematopoietic cells Signup and view all the answers

What is a significant risk for HSC transplant recipients due to immunodeficiency?

Heightened susceptibility to infections Signup and view all the answers

What is a major barrier to the successful grafting of embryonic stem cells?

Their alloantigenicity and rejection by the immune system Signup and view all the answers

What constitutes the primary mechanism causing graft versus host disease (GVHD)?

Grafted immune cells attacking host cells Signup and view all the answers

What is the consequence of progressive arterial lesions of graft arteriosclerosis on graft parenchyma?

The parenchyma is replaced by nonfunctioning fibrous tissue. Signup and view all the answers

How can induced pluripotent stem (iPS) cells be generated?

By transduction of specific genes into adult somatic tissues Signup and view all the answers

How does MHC matching influence renal allograft survival?

Only some MHC alleles affect survival rates. Signup and view all the answers

What is the primary genetic consideration in allogeneic HSC transplantation?

Matching at all major histocompatibility complex (MHC) loci Signup and view all the answers

What factor greatly increases the risk of developing B cell lymphomas after an HSC transplant?

Infection with Epstein-Barr virus Signup and view all the answers

What is the primary function of IL-2 in relation to T lymphocytes?

To stimulate the differentiation and proliferation of T lymphocytes. Signup and view all the answers

What role does the immune synapse play in T cell signaling?

It facilitates prolonged and effective T cell signaling. Signup and view all the answers

Which of the following is not a component of the signaling machinery assembled at the immune synapse?

Extracellular matrix proteins Signup and view all the answers

In the context of IL-2's actions, which statement is true regarding its relationship with regulatory T cells?

IL-2 enhances the survival of regulatory T cells and maintains their function. Signup and view all the answers

What is the significance of signaling molecule turnover at the immune synapse?

It contributes to the termination of T cell activation. Signup and view all the answers

Which aspect of MHC matching is emphasized in the context of renal allografts?

Certain MHC alleles are more important for outcomes than others. Signup and view all the answers

What is the primary mechanism by which T cells of a graft recipient recognize intact MHC molecules in the graft?

Direct presentation of alloantigens Signup and view all the answers

In indirect presentation, which molecules are crucial for the recipient T cells to recognize graft MHC molecules?

Donor peptides bound to recipient MHC Signup and view all the answers

How do alloreactive T cells recognize donor MHC molecules despite the presence of self MHC–restricted T cells?

By the distinctive polymorphic residues of the allogeneic MHC Signup and view all the answers

Where does the T cell response to an organ graft typically initiate?

In lymph nodes that drain the graft Signup and view all the answers

What role do donor APCs play in graft rejection?

They present unprocessed allogeneic MHC to recipient T cells Signup and view all the answers

Which T cell subsets are primarily involved in recognizing allogeneic class I and class II MHC molecules?

CD8+ for class I and CD4+ for class II Signup and view all the answers

Which of the following correctly describes the nature of the peptides bound to MHC molecules in direct recognition?

Peptides can be derived from both donor and recipient proteins Signup and view all the answers

What is a significant difference between direct and indirect recognition processes?

Direct recognition relies solely on polymorphic residues without peptides Signup and view all the answers

Study Notes

Graft Rejection

Grafts from offspring of different inbred animal strains will be rejected by either parent strain.
Rejection occurs because the offspring inherit a unique combination of MHC alleles from both parents.
This uniqueness leads to the offspring expressing MHC molecules that appear foreign to either parent.

T Lymphocyte Maturation

Negative selection eliminates developing lymphocytes whose antigen receptors bind strongly to self-antigens.
Negative selection is important to prevent autoimmune reactions.
Factors contributing to negative selection include:
- Failure to productively rearrange the TCR β gene,
- Failure to be positively selected by self MHC molecules,
- Self antigen-induced negative selection.

MHC Genes

MHC genes code for proteins that present antigens to T cells.
The polymorphic class I and class II MHC molecules display peptides for recognition by CD8+ and CD4+ T cells, respectively.
Different MHC alleles bind and display different peptides, meaning individuals can present different peptides even from the same protein antigen.
Individuals inherit MHC alleles from both parents, maximizing the number of MHC molecules available to bind and present peptides.

MHC Structure and Location

In humans, the MHC is located on the short arm of chromosome 6, spanning about 3500 kilobases (kb).
Three class I MHC genes (HLA-A, HLA-B, HLA-C) encode for three types of class I MHC molecules with the same names.
Three class II HLA gene loci (HLA-DP, HLA-DQ, HLA-DR) each code for a heterodimer of α and β polypeptides.
The set of MHC alleles present on each chromosome is called an MHC haplotype.

Direct and Indirect Alloantigen Recognition

Allogeneic MHC molecules of a graft can be recognized by recipient T cells through two mechanisms: direct and indirect presentation.
Direct presentation occurs when recipient T cells recognize intact MHC molecules on the graft.
Indirect presentation involves recipient T cells recognizing peptides derived from donor MHC proteins, presented by recipient MHC molecules.

Molecular Basis of Direct Recognition

MHC molecules on cell surfaces typically contain bound peptides, which can contribute to the structure recognized by alloreactive T cells.
Even if these peptides are shared between donor and recipient, their presentation by allogeneic MHC molecules creates a unique complex.
Alloreactive T cells can be activated by the polymorphic amino acid residues of the allogeneic MHC molecule alone, regardless of the peptide.

Activation of Alloreactive T cells

The T cell response to an organ graft can begin in the lymph nodes draining the graft.
Donor-derived APCs (such as DCs) can migrate to lymph nodes and present allogeneic MHC molecules to recipient T cells, triggering direct allorecognition.
This process can lead to graft rejection, which can involve damage to graft vasculature and parenchyma replacement with fibrous tissue.

Influence of MHC Matching on Graft Survival

Matching MHC alleles between donor and recipient significantly improves renal allograft survival, especially for deceased donor grafts.
Matching has a less dramatic impact on survival for live donor grafts.
Specific MHC alleles have varying importance in determining graft outcome.

Biologic Actions of Interleukin-2 (IL-2)

IL-2 acts as an autocrine growth factor for T lymphocytes, stimulating their survival, proliferation, and differentiation.
IL-2 promotes the survival and functionality of regulatory T cells, influencing immune responses.
IL-2 can act in an autocrine, paracrine, or endocrine manner.

The Immune Synapse

This specialized structure forms between a T cell and an APC displaying the antigen.
It facilitates T cell signaling by assembling TCR complex, coreceptors, costimulatory receptors, and adaptors.
The immune synapse directs the delivery of secretory granules and cytokines from the T cell to the target cell.
It also contributes to the termination of T cell activation by degrading signaling molecules.

Immunosuppressive Drugs

Immunosuppressive drugs are used to prevent or treat graft rejection.
These drugs can target different components of the immune system, such as T cell activation, proliferation, or cytokine production.

ABO Blood Group Antigens

ABO antigens are carbohydrate structures found on red blood cells.
Different individuals express different combinations of these antigens, determining their blood type.
ABO incompatibility can lead to transfusion reactions, as antibodies against foreign antigens can trigger hemolysis.

Immunologic Complications of Hematopoietic Stem Cell Transplantation (HSCT)

HSCT is a procedure used to treat diseases affecting hematopoietic lineages by replacing defective cells with donor cells.
Allogeneic HSCT requires careful MHC matching between donor and recipient to prevent graft rejection.
Graft-versus-host disease (GVHD) can occur when donor T cells attack host tissues.
Immunodeficiency is a complication of HSCT, increasing susceptibility to viral, bacterial, and fungal infections.

Induced Pluripotent Stem (iPS) Cells

iPS cells offer potential for tissue repair, particularly in organs with limited regenerative capacity.
iPS cells can be derived from adult somatic tissues by genetic reprogramming.
They hold promise for overcoming alloantigenicity, as patient-derived iPS cells are unlikely to be rejected.
MHC gene removal from allogeneic embryonic stem cells via CRISPR-Cas9 technology is another strategy being explored.

Regulatory T Cells (Tregs)

Tregs play a key role in maintaining immune tolerance by suppressing immune responses.
They can suppress immune responses via:
- Production of immunosuppressive cytokines,
- Reducing APC ability to stimulate T cells,
- Consuming IL-2.

Chimeric Antigen Receptor (CAR) Tregs

CAR Tregs are genetically modified Tregs expressing chimeric antigen receptors.
These receptors allow Tregs to target specific antigens, expanding their therapeutic potential.
CAR Tregs are being investigated for their potential to treat diseases like cancer and autoimmune disorders.

Genetic Modifications in Pigs for Organ Transplantation

Pigs are being genetically modified to overcome immunological barriers for xenotransplantation (organ transplantation from one species to another).
These modifications aim to reduce pig MHC expression and prevent immune rejection by human recipients.

Pigs with Modified Genes for Experimental Transplantation

Pigs with numerous gene modifications are providing organs for experimental transplantation into nonhuman primates.
These studies aim to assess the safety and efficacy of xenotransplantation in a preclinical setting.

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Description

Explore the mechanisms behind graft rejection in immunology, focusing on the unique MHC alleles from different inbred animal strains. Understand T lymphocyte maturation, including negative selection and its role in preventing autoimmune responses. Delve into the functions of MHC genes and their importance in T cell activation.