John Bovill Immune Rejection

Immune Rejection

What Is Immune Rejection?

• Immune rejection can occur during all kinds of transplants. When foreign substances and objects enter the body, the immune system responds to the perceived invasion. Immune cells identify things in the body through recognition of antigens that are on the surface of different molecules. After a transplantation, whether it is blood or a solid organ, the body of the transplant recipient will recognize the transplanted tissue as foreign. This results in the recipient's immune system attacking the transplanted tissue in a similar way it would attack a virus, bacterial infection, or toxic substance that had entered the body.
• Immune rejection exists in three forms, with varying severity: (17)

1. Acute rejection: Can occur any time within a week to around three months after transplantation. All recipients experience some degree of acute rejection.
2. Hyperacute rejection: Occurs within a few minutes of transplantation and can be fatal if not treated immediately. For example, this occurs when a patient is given a blood transfusion of a non-compatible blood type.
3. Chronic rejection: Can take place over many years. This leads to a slow accumulation of damages to a transplanted tissue or organs, and could necessitate additional transplantations.

What Causes It?

• Immune rejection is caused when the human immune system recognizes a transplant as foreign and subsequently attacks it. This is a result of the mechanism that immune cells use to identify other cells, proteins, molecules, etc.
• Immune cells use antigens on the surface of various things to determine the object as "self" or "foreign".
  • An object that is determined as "self" is allowed to persist in the body and does not warrant further attention from immune cells.
  • An object that is identified as foreign is attacked by the various immune cells in the body, and disposed of through various mechanisms that have evolved for dealing with pathogens.
  • Pathogens are anything that can potentially cause disease.
• In the human body, the antigens used to recognize something as self or foreign are called human leukocyte-associated (HLA) antigens. These are the MHC molecules in humans. Each individual has a collection of HLA molecules on the surface of their cells that their immune system is capable of recognizing.
• HLA molecules are highly polymorphic, meaning they have many different alleles within the population.
• When donating tissue, these antigens must be taken into account. The donor and recipient in a transplantation are matched by their HLA molecules to reduce the chances of immune rejection.
  • When the HLA molecules of donated tissue do not match those of the recipient, immune rejection occurs.

Avoiding Immune Rejection

• Ideally, every transplantation would occur between two people that have perfectly matching HLAs. Because there are so many different alleles in the human population, this often isn't possible.
• This requires transplantations to match HLA antigens as best as possible. As the number of matching HLAs between a donor and transplant recipient increases, the likelihood of a successful transplantation also increases.
• During the initial transplantation, risk of immune rejection is often reduced substantially by placing donors on immunosuppressive drugs to lessen acute rejection symptoms.
• Even after a successful transplantation, a lack of perfectly matched HLA antigens can lead to chronic immune rejection.
  • This form of immune rejection may not manifest for numerous years, but has slow, deleterious consequences for a transplant recipient. Because this form of immune rejection can take such a long time to show symptoms, it is quite difficult to manage, and can lead to a need for a second transplant.

Immune Rejection in Bone Marrow and Blood Donations

• One type of stem cell therapy that is currently possible involves transplantation of hematopoietic stem cells into a host. By providing a patient with a pluripotent stem cell, it is possible to replace the population of blood cells inside a patient who, for a number of reasons, may have deficient counts of blood cells that are essential for immunity. (6 & 10)
  • Matching HLAs becomes incredibly important for patients who are receiving a donation of bone marrow derived cells.
  • In many treatments involving bone marrow transplantation, the recipient of the transplant has some deficiency or mutation that causes their immune system to function at a suboptimal level.
    • One way to correct for this is to ablate the bone marrow of the transplant recipient and then subsequently donate hematopoietic stem cells.
    • Ablation of bone marrow causes the patient's resident population of white cells, which are essential in immune function, to be wiped out. They are then replaced by the donor's cells, which reproduce within the host's body.
    • When successful, this essentially allows a whole replacement of the transplant recipient's immune system. This transplant has massive potential, as it can theoretically transfer disease immunity from one person to the next. However, the fact that the host's original bone marrow derived cells were ablated and entirely destroyed can create a massive problem if the patient experiences Graft-vs.-Host Disease.

Graft Vs. Host Disease

http://www.regimmune.com/product-pipeline/gvhd/

• Graft-vs.-Host Disease (GVHD) can happen during nearly any transplantation, but is especially prevalent in bone marrow transplantations. (4)
  • GVHD occurs when transplanted white blood cells identify cells in the patient's body as foreign.
    • The most commonly effected organs are the skin, liver, and intestines.
  • The complication can occur shortly after a transplant (acute GVHD) or much later (chronic GVHD).
  • GVHD functions similarly to immune rejection, but instead of the patient's immune mechanisms attacking a transplant, the transplanted tissue has carried some immune cells into the patient's body, which then treat it as if it is foreign.
  • The risk of GVHD drops with better HLA matches, but if experienced, it can be very difficult to treat.
  • In the case of a bone marrow transplant, this disease is especially dangerous.
    • In standard transplantations, the immune system of the patient remains intact, and they are capable of defending themselves to some degree against the donor cells.
    • When the patient has had their entire white blood cell population decimated, and then experiences GVHD, the patient has no source of internal defense against the donor white blood cells that are attacking their body.
• While bone marrow donations could potentially help confer resistance from one person's immune system to the next, this is not the case. Because GVHD can cause such serious issues during transplants, and it is quite difficult to find a donor that is a perfect match, widespread bone marrow donations to confer immunity across entire populations are not seen, and the procedure is typically only done in patients with few other options.

Embryonic Stem Cells and Immune Rejection

• This study (5) shows that embryonic stem cell lines may have a lower chance of immune rejection than adult stem cell lines.

Table of Contents

• Stem Cell Overview
• Potential Uses
  • Stem Cells As a Research Tool
  • Cell Based Therapy
• Obstacles
  • Immune Rejection
  • Difficulties in Creating Stem Cells
• References