Dear IBCEC
There is no FDA approved treatment for PP/SPMS
Here is a sample of what could be a cure for PP/SPMS.
Multiple Sclerosis : Disease Features:
Myelin sheath degradation by:
Oligodendrocyte (OLG) Apoptosis AND myelin sheath complement Opsonization
The cells involved
Antigen –Specific antibody producing B-cells,
Antigen –Specific Cytotoxic T-Cells(ASCD8),
Antigen –Specific Helper T-cells(ASCD4),
Microglia,
Macrophages and
Oligodendrocytes(OLG-likely the self antigens)
Reasoning CURE
Normal patients have waiste-myelin in their cerebral spinal fluid(CSF). Microglia and macrophages absorb it. Normal patients have no method of controling / removing self antigen-specific B-cells but upon contact with self antigen the B-cells do not become plasma cells to produce antibody. Nothing serious happens. Normal patients complement pathways are not activated by the myelin sheath(self antigen) anywhere. In patients with the disease, B-cells are only activated in the CSF indicating antigen-specific T-cell dependency.
Hence, the logic suggests there is an evolutionary reason Normal patients are safe and that the simplest disease explanation is a possible genetic susceptibility to a Thymus apoptosis error in the negative selection process from double positive self antigen specific naive ASCD4 and ASCD8 T-cells. (Thymus didn't kill the high concentration naive ASCD4,ASCD8 T-cells)
The occurrence of the error could be latitudinal or seasonally sensitive. It is suggested , when auto immune disease occurs in this fashion that patients are vaccinated against themselves causing memory T-cells to be involved allowing for prolonged damage. It is further suggested that BAIT BOX's might cure these diseases. In the case of MS the BBB may act to establish the BAIT BOX allowing ablation of a reduced part of the Immune System as described below.
Therefore : only Antigen –Specific Cytotoxic T-Cells(ASCD8), Antigen –Specific Helper T-cells(ASCD4), OR Oligodendrocytes(OLG)-(likely the self antigens) are involved in initiating Multiple sclerosis.
When the ASCD8 or ASCD4 cells encounter the antigen rich OLG they start apoptosis.
If the culprit is the ASCD4 helper T-cell, then cytokines are released which foster a serious immune response that includes complement triggering with C3b and C5b-9 (MAC) and self antigen- specific B-cell activation(CD20, CD27mem). The antibody produced assists in opsonization of the myelin sheath and the complement process . This eventually is normally modulated and subsides allowing for a remission until some other ASCD4 cells encounter another susceptible OLG which then also requires modulation— this demonstrates exacerbating/remitting disease(RRMS). If the culprit is the ASCD8 cytotoxic T- cell, no exacerbation happens but no remission either. Progressive disease(PP/SPMS) occurs and memory ASCD8-cells continually exist in the CSF([email protected]) causing OLG apoptosis leading to myelin sheath reduction. This continuity is likely perpetuated by CCSVI (chronic cerebrospinal venous insufficiency) which exists in many RRMS and PP/SPMS patients. If both culprits exist then Secondary Progressive disease may occur(SPMS).
The Cure
There is currently no effective treatment for PP/SPMS,
Based on this understanding, I believe a cure may exist for PP/SPMS. If there are high concentrations of ASCD8 cells around the local OLGs relative to blood concentrations then removing them from the CSF may be efficacious . By using spaced intrathecal injection treatments, you could selectively kill all cytotoxic T-cells(including ASCD8) in the CSF and halt the disease process.
CSF is created 0.4ml/min by the choroid plexuses. The volume of the CSF is near 150 ml yielding a replacement time of 6 hrs. The blood flow to the Blood Brain Barrier(BBB) is 750 ml/min allowing the plexuses to contact all blood T and B cells(5.5 billion) every 10 minutes. The number of leukocytes ( all T-cells + all B-cells) in the CSF is normally 200,000 to 500,000. If PP/SPMS disease is chronic with no immune relapsing/remitting process , then likely the signals that allow T or B-cells to quickly cross the BBB in the plexuses is minimal, indicating that intermittent removal of all cytotoxic T-cells(including high concentration ASCD8) in the CSF MIGHT BE A CURE.
Example
Dr. Mark Freedman used this removal idea 10 years ago in Ottawa using Cyclophosphamide for a whole Immune System Reboot which was dangerous. Johns Hopkins also uses Cyclophosphamide (Hi-Cy) to eliminate all ASCD8, ASCD4 and other immune cells to stop extreme RRMS. Cyclophosphamide treatment is immune ablative and risky. Less aggresive immune cell control is also being currently done using drugs like Alemtuzumab(Campath), and Tysabri. Campath is an antibody to CD52(which is found on the surface of many immune cells) used to treat RRMS but has no effect on PP/SPMS. TYSABRI prevents most immune cells (ASCD8,ASCD4) from entering the CSF which will not take care of the current CSF ASCD8 population and during the course of treatment may hamper the brains ability to respond to infection and could cause PML. It also has little effect on PP/SPMS. Injecting Campath provides a complement-mediated lysis of T and B cells, macrophages etc. It is sometimes used for transplant tolerance and is now also being used for autoimmune tolerance. It has been revealed by Anna Valujskikh that T Cell Memory is a Barrier to Transplant Tolerance (“Frontiers in Nephrology: T Cell Memory as a Barrier to Transplant Tolerance”---- Department of Immunology, the Cleveland Clinic Foundation). Because memory ASCD8 cells are most likely involved with PP/SPMS and Campath may not kill memory T-cells it consequently has little effect on PP/SPMS. A good opportunity may exist to help PP/SPMS if you could safely save the entire immune system and just lyse CD8 cells in the fluid that bathes the Central Nervous System(CSF). If/when lysis of CD8 memory T-cells using the intrathecal antibody(anti-CD8) approach is not efficacious then perhaps we need a new technique to safely CURE THE DISEASE.
Involved in Bioengineering, I know a way exists to use nano-gold covalently bound to Fc arms of monoclonal antibodies to CD4 or CD8 epitopes. Exposing the T-cells to these antibodies through an intrathecal injection and then administering non-invasive short wave(15 Mhz) radio transmission(therm med llc, erie penn) would then kill all cells attached to the antibodies(assuming that memory cells express a surface protein that attracts a CD8 antibody) . The effect of necrosis vs apoptosis needs to be clarified. The current use of an antibody-dependent complement-mediated lysis of T and B cells supports necrosis as a possible approach. The treatments are minimal in number and restricted to the CSF. The safety and possible efficacy of this technique could be accomplished quickly using an animal with EAE. A physician using antibody, nano-gold and radio waves to kill cells is Steven Curley(preclinical), ([email protected] 713-794-4957). A few Intermittent treatments may be necessary to remove all memory antigen specific T-cells that may continually cross the BBB. The Thymus would have to make another---- apoptosis--- mistake to refurbish these T-cells.
To complete the cure of SP/PPMS, an oligodendrocyte stem cell approach may now be available using primarily those stem cells carrying a CD140a marker( Fraser Sim) to repair damage.
(http://www.nature.com/nbt/journal/v29/n10/full/nbt.1972.html ) . CD140a identifies a population of highly myelinogenic, migration-competent and efficiently engrafting human oligodendrocyte progenitor cells. Microarray analysis of CD140a+ cells revealed overexpression of the oligodendroglial marker CD9, suggesting that CD9+/CD140a+ cells may constitute an even more highly enriched population of myelinogenic progenitor cells.
END OF SAMPLE
Very Kind Regards,
Gerry Scally
