Transplantation & Transfusion...

[BlackNDecker]

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This is not a Step I question, this is a Path. question...

Anyone care to explain why transfusing the donor blood prior to transplantation(BM or organ) results in TOLERANCE, whereas multiple transfusions result in SENSITIZATION?

I think I understand SENSITIZATION resulting from...
Th2 cells interacting with infused donor Ag(whole blood) >>> cytokines >>> B cell activation >>> incr. plasma cells specific for donor MHC I & II...causing a secondary immune response(type II hypersensitivity/Hyperacute rejection) when the BM/organ is transplanted.


...however, I'm having trouble seeing the TOLERANCE aspect.

 

[BlackNDecker]

To be more correct, I should have stated that it is the recipient's APCs(notably B cells) that present the donor Ag to Th2 cells >>> IL-4, IL-10 >>> plasma cell activation >>> Hyperacute rejection

Still unclear on Tolerization...

 

[RS6]

This is a great question. First off, I will say that no one really knows why organ tolerance is achieved with prior blood transfusion. However, there are several hypotheses and the following is the most likely.

In order for T helper cells (CD4+) to activate and undergo clonal expansion, their must be a proper interation between the T cell receptor (TCR) and its own HLA class II MHC antigen located on an antigen presenting cell (APC). This recognition causes production of sufficient IL-2, which is necessary for a full immune response with T cell clonal expansion and B cell activation. But substantial amounts of IL-2 need to be produced and this can only occur with proper costimulatory molecule interactions, mainly stimulation of CD28 on the T cell by the B7 molecule on the APC. In addition the duration of contact between the APC and the T cell is thought to determine the T-cell response, again through the production of sufficient IL-2. T cells recognizing the antigen-class II MHC complex on the APC but not receiving the costimulatory signal become partially activated and have reduced IL-2 production. Without sufficient IL-2 production, they enter an anergic state in which they are functionally unresponsive to further exposure to that antigen. This is the mechanism by which the antirejection drugs cyclosporine and tacrolimus work. Remember that these drugs inhibit the production of IL-2 by binding to intracellular proteins preventing IL-2 transcription and subsequent secretion. Therefore, this may explain why there doesn't seem to be much of a benefit in prior transfusion tolerance since the advent of these drugs.

Based on this theory...why then does blood transfusion lead to improper costimulation of T cells?

Antigens introduced IV, such as blood, may be phagocytosed and presented by macrophages in the blood, liver, or spleen, which do not readily express the B7 costimulatory molecule on their cell surface. These are what people call "nonprofessional" APCs. This will then lead to improper IL-2 production and anergy may result.

Another hypothesis is that the donor transfused WBCs also present antigen to the recipient T cells, this is called indirect presentation. These WBCs may not have the proper HLA MHC II molecule or B7 molecule causing improper recipient T cell activation causing reduced levels of IL-2, also resulting in anergy.

This is way beyond the scope of step 1. The key here is learning the importance of costimulatory molecules in activating the immune system and that improper stimulation can lead to anergy/tolerance. I would also learn the mechanisms of how cyclosporine and tacrolimus work. Also know the types of organ rejection, their mechanisms and their time periods.

good luck.......

 

[BlackNDecker]

First off, thanks for the indepth response. I know this is beyond the scope of Step 1, but the allopathic forums are worthless for talking about subject related material. Having said that...
So when you transfuse the graft recipient with donor blood prior to transplantation, it's like rolling the dice:

If the RECIPIENT's T cells are presented Ag by "professional" APCs (w/ B7 co-stim.) they will produce IL-2, IL-4, IL-10, IL-13 >>> Ab to graft >>> hyperacute rejection.

If the RECIPIENT's T cells are presented Ag by APCs lacking B7(decreased IL-2) then it will be more probable that there will be an anergic response >>> host "chimerism"

Would this be a correct interpretation?

 

[BlackNDecker]

This is the mechanism by which the antirejection drugs cyclosporine and tacrolimus work. Remember that these drugs inhibit the production of IL-2 by binding to intracellular proteins preventing IL-2 transcription and subsequent secretion. Therefore, this may explain why there doesn't seem to be much of a benefit in prior transfusion tolerance since the advent of these drugs.

We learned in Immunopath that cyclosporine binds EXTRACELLULARLY to the CD3 subunit of the TCR (preventing signal transduction, IL-2 production, w/ no effect on Tsupressor cells allowing them to inhibit the T cell mediated Ab response). Can you clarify this as well?

Thanks in advance...

 

[BlackNDecker]

Since you seem to know your Immuno...

Why is IVIg and plasma acceptable treatment for Bruton's Agammaglob. & CVID, but causes anaphylaxis in pts with IgA deficiency? Is it because of an increased production of IgE in compensation? And if so, then shouldn't you see anaphylactic responses in pts w/ Wiskott-Aldrich Syndrome who receive transfusions due to increased IgE?

 

[RS6]

Tolerance question:

You have it right on. Remember that tolerance is not always effective and it kind of is like rolling the dice. This is why this type of therapy is controversial.

Cyclosporine question:

Normally when the TCR is stimulated, it causes intracytoplasmic calcium levels to increase. This causes the activation calcineurin, a phosphatase that activates NFAT. The activated NFAT goes into the nucleus where it binds to AP-1 to produce an active transcription factor. This causes the subsequent transcription of IL-2 and other cytokines as well as the clonal exapansion of the T cell. My understanding is that cyclosporine binds to an intracytoplasmic protein called cyclophillin A. Once these to molecules are bound they bind to calcineurin which effectively block the activation of NFAT. Therefore, the proper transcription factor is never formed and IL-2 and T cell expansion never occur. I have never heard of cyclosporine interacting with the CD3 subunit of the TCR. You might want to do a drug literature search on this but I'm fairly certain that the aforementioned mechanism is the one most people agree with. Tacrolimus (FK506) acts in a similar manner to cyclosporine except it binds to an intracytoplasmic protein called FKBP (FK binding protein) and it too inhibits the activation of NFAT by binding calcineurin.

IVIG question:

From my understanding, IgE antibodies to IgA have been reported to cause severe transfusion reactions in IgA-deficient patients. Therefore, any patient with IgA deficiency but normal IgE levels has the potential to have an anaphylactic reaction. This includes two types of people:

1.) selective IgA deficient individuals
2.) those patients with CVID who have a deficiency of IgA

Remember CVID patients can have a variable immunoglobulin picture and only those with low levels of IgA will be effected. Other CVID patients will not be effected but unless you have a plasma electrophoresis staring in your face, I would be cautious.

This is not a problem for patients with Bruton's agammaglobulinemia or severe combined immunodeficiency (SCID) because they don't have the ability to form IgE in the first place so there can never be an anaphylactic reaction. So even if you had all the anaphylactic agents in the world injected into these people, they would never anaphylax because they don't have IgE.

Also, you do not see any anaphylactic reactions in Wiskcott-Aldrich syndrome patients because you have elevated levels of IgA. Remember they have elevated IgA, normal IgE, and low IgM. So transfusing these patients with IgA containing IVIG would not cause a reaction because your body is used to seeing IgA, regardless of IgE level.

Therefore, only those individuals who have never seen IgA before and have a competent IgE concentration have the potential to have an anaphylactic reaction.

hope this helps and good luck........

 

[BlackNDecker]

hope this helps and good luck........

Thanks, you've answered every puzzling immuno question I have(for now)... So when does your immunology book come out? 😛

 

[RS6]

LOL....I happened to work in a transplantation lab for 2 years as an undergrad and during my year off before I started medical school. So I had to have a firm knowledge of tolerance in order to present posters and abstracts and not look like a fool. It happenned once and I vowed never to let it happen again. But can you believe I didn't honor my immunology block first year??? It just goes to show that med school exams are based purely on what teachers want and do not test enough pathophysiology. Or maybe I was over confident. Oh well....

Anyway, you ask some good questions. Keep them coming and good luck in your studying.

 

[BlackNDecker]

We learned in Immunopath that cyclosporine binds EXTRACELLULARLY to the CD3 subunit of the TCR (preventing signal transduction, IL-2 production, w/ no effect on Tsupressor cells allowing them to inhibit the T cell mediated Ab response).

My mistake...I was confusing cyclosporine with orthoclone. We were taught that orthoclone binds extracellularly to the CD3 receptor...

 

[manta]

thanks guys! that ivig thing was giving me trouble too. i think i finally got it. 😀