GvHD Prophylaxis and Treatment

GvHD is the most frequent post allogeneic stem cell transplant complication and is a major cause of morbidity and mortality.

 


1.    GvHD Prophylaxis


Drugs used in GvHD prevention or prophylaxis include a combination of the calcineurin inhibitors Cyclosporin or Tacrolimus with a short course of Methotrexate (MXT).

 

Methotrexate

Methotrexate (MXT) is a folic acid antagonist that inhibits dihydrofolate reductase, a key enzyme in the synthesis of the amino acids serine and methionine, thereby interfering with the formation of DNA. Methotrexate is often recommended for GvHD prophylaxis in patients considered to be at high risk of disease reoccurrence.

 

Cyclosporin

The ability of Cyclosporin to inhibit T lymphocyte function and suppress the early response to antigenic stimuli makes it useful for GVHD prophylaxis. Studies have shown that Cyclosporin used in combination with MXT is more efficacious than either drug used alone.

 

Cyclosporin-A is a Calcineurin inhibitor. Calcineurin is a protein phosphatase also known as protein phosphatase 3. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate Calcineurin. Calcineurin then activates NFAT (Nuclear Factor of Activated T-cells) by dephosphorylating it. Upon activation, NFAT is translocated into the nucleus where it upregulates the expression of IL-2 which, in turn, stimulates the growth and differentiation of T cell response. Cyclosporin binds to the cytosolic protein Ciclophilin and the resulting complex binds to and inhibits Calcineurin.

 

Tacrolimus

Like Cyclosporin, The ability of Tacrolimus to inhibit T lymphocyte function and suppress the early response to antigenic stimuli makes it useful for GVHD prophylaxis. Tacrolimus is a Calcineurin inhibitor which is similar in action to cyclosporin. Tacrolimus prevents NFAT dephosphorylation by complexing with the immunophilin FK binding protein 12 (FKB12) creating a new complex which interacts with and inhibits Calcineurin, thereby inhibiting the expression of IL-2 which, in turn, inhibits the growth and differentiation of T cell response.

 

In a randomised prospective trial, use of Tacrolimus with short course MTX was shown to be superior to the use of Cyclosporin and MXT in GvHD prophylaxis in a group of HLA matched sibling transplants.

 


2.    GvHD Treatment


For patients with GvHD, their primary response to GvHD therapy is one of the most important predictor of long term survival. The best initial therapy is a dose of Methyl-prednisolone.  Patients refractory to this primary treatment are treated with a secondary course which includes higher doses of Methylprednisolone or other immunosuppressive drugs not already used as induction therapy, including Tacrolimus, MMF or Sirolimus, ATG, monoclonal antibodies.

 

Primary treatment

Primary treatment of GvHD is often trough the use of Methylprednisolone.

Methylprednisolone

Methylprenisolone, a synthetic variant of Prednisolone, is a Glucocorticoid. i.e. a steroid hormone which binds to the glucocorticoid receptor, activation of which leads to up-regulation in the expression of anti-inflammatory proteins and down-regulation in the expression of pro-inflammatory proteins.


 

Secondary treatment

Secondary treatments include Tacrolimus, MMF or Sirolimus, ATG and monoclonal antibodies.

 


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