The blood brain barrier (BBB) is a mechanism by which high molecular weight molecules and ions are prevented from passing from the blood to the brain tissue. The cerebral capillaries exhibit the BBB. Therefore, very few immunological cells pass through this barrier

Lack of Conventional Lymphatic Drainage

The lymphatic system in the brain is very different from the lymph system in the rest of the body. Because the lymph system does not drain directly into the blood stream, there are fewer chances for the lymphatic system to recognize non-self cells.

MHC system

The Major Histocompatability Complex is an antigen system which recognizes non-self cells and presents cell-surface peptides and proteins to other immunological cells. Levels of MHC antigens exist at much lower level in an intact BBB, and the absence of MHC class II cells in the Brain means that this system is not used to recognize foreign particles and cells in the brain. However, it is thought that microglial and astroglial cells may have this capability. There is also evidence that CNS neurons are refractory to MHC antigen induction (Sloan 346). Therefore, while the MHC Antigen recognition in the brain is greatly reduced, it is present at low levels. (see photo) For an extensive overview of the immune system, click here.

Pharmacological immunosuppression is the most widely used method of immunosuppressive therapy for xenotransplantation.  The most common immunosuppressive drug used for treatment is Cyclosporin-A.  Cyclosporin-A (CsA) works by blocking T cell mediated immune response, directly affecting the immune system (Borlongan 298).  While CsA has been shown very effective at preventing graft rejection, it unfortunately has the disadvantage of harboring numerous side effects.  These side effects include nephrotoxicity, seizures, parasetesia, visual hallucinations, encephalopathy, and cortical blindness (Borlongan 299).  Unfortunately, short-term treatment with CsA does not support long-term survival.  However, if treatment time surpasses the time required for BBB reformation, long-term survival is supported. Since CsA is so toxic, there are many other immunosuppressants under investigation.  Recently drug combinations such as lower doses of CsA with steroids and azothiaprone have come into use instead of high CsA doses, and as alternatives to CsA obtain FDA approval, CsA will no longer be the drug of choice for immunosuppression.
 

Masking MHC-1 Antigens

A different method of immune response circumvention is the masking of MHC-1 antigens with F(ab)₂ monoclonal antibody fragments.  The rationale behind this method is that monoclonal antibodies will allow tolerance to autoantigens and solid organ transplants (Borlongan 301).  The fragments used specifically bind to MHC class I antigens and therefore immunosuppress the CNS at the molecular level.  The antibody fragments are utilized either by pre-incubating the donor cells with the fragments or by injecting the site of transplantation with the antibody fragments.  This method is the one currently used for the clinical trials of the transplantation of porcine cells into human Parkinson's Disease patients.

Bead Encapsulation

Another method of transplanting dopamine-secreting cells while evading immune response involves the utilization of DA-secreting cells encapsulated by a polymer (Borlongan 300).  This is accomplished either by microencapsulation-coating single cells or small clusters with a thin polymer layer, or macroencapsulation-filling a hollow fiber with cells or tissue and sealing the ends.  The major advantage of this method is that it eliminates the need for immunosuppressants.  This method of drug delivery has been used for patients suffering with chronic pain syndromes, but has yet to be utilized for Parkinson's Disease.
 

Utilization of Microcarrier Beads

Microcarrier beads are a way to provide a matrix for grow and thrive.  Early studies have shown that providing a matrix like microcarrier beads for cells to attach and grow may maintain long term viability of the cells.  In addition, cotransplantation of microcarrier beads may allow the  absence of immunosuppression.  However, it is unclear why this is the case. It may be that the binding of cells to the polymer beads disrupts the function of MHC antigens, but further studies are required to elucidate the mechanism of this method.
 

Sertoli Cells as a Graft Source

Sertoli cells secrete many beneficial growth and maintenance factors as well as immunosuppressive factors. As a result, enhanced survival may be found with the cotransplantation of Sertoli cells and neural cells. The immunosuppressive effect of Sertoli cells is akin to CsA. However, the Sertoli cell secretions do not affect IL-2 receptor activity. Like cell encapsulation and polymer work, this mode of immune system circumvention is still in the early stages of development.

Genetically Engineered Donor Tissue (In vitro and ex vivo gene therapy)

With the level of sophistication that molecular genetics developed in recent years, it has been possible to utilize genetic manipulation for theraputics in medicine. In this area, one can now use retroviral vectors or plasmid transfection to modify genes in donor tissue or cells (Borlongan 302). While this looks like a promising view of treatment, experimental results have been mixed. One study genetically removed the MHC antigens from the cell surface of the neurons. There was no increase in graft survival. A more promising technique utilizes genetic manipuation of a recipients own cells to derive cells for treatment. In this case, one will face little immunological response because of the relatedness of the donor and recipient.