Conceptually the best way to treat multiple sclerosis is to specifically inhibit the immune response against the myelin sheath, while leaving the immune response against other proteins intact.  Additionally, the best way to treat it, is also to induce regeneration of neurons and central nervous system components that have already been damaged, perhaps through the use of stem cells.

Successful use of stem cell therapy in multiple sclerosis is believed to occur because the fat contains numerous cell populations that inhibit pathological immune responses, such as T regulatory cells (whose function is suppressed in multiple sclerosis), while at the same time containing stem cells, especially mesenchymal stem cells, which can repair damaged tissue.

The reprogramming of the immune system to selectively stop attacking one protein, or a series of specific proteins is called “immunological tolerance”.  Originally the concept of tolerance came from experiments by the scientists Billingham-Brent-Medawar decades ago who demonstrated that if two genetically distinct animals had shared circulation during embryonic development, when the animals reached adulthood they would readily accept tissue grafts from each other but reject grafts from others.  In other words the animals were made “tolerant” to each other. 

This concept of selectively “teaching” the immune system that it should not attack a specific antigen is how approaches such as the myelin basic protein DNA vaccine developed by Bayhill Therapeutics seems to work.  This vaccine, called BHT-3009, was demonstrated to induce antigen-specific immune modulation in multiple sclerosis patients in a Phase I/II study, and was subsequently demonstrated to be capable of causing a 50-61% reduction in new lesion formation as detected by MRI and profound reduction of anti-myelin antibodies in a subsequent Phase II study in multiple sclerosis patients.  DNA vaccines seem to work in part through inducing interferon beta, which seems to be involved in shifting of the T cell cytokine production profile away from Th1 and Th17, although this is controversial.

Another way to “trick” the immune system into selectively not attacking an antigen is to provide the antigen orally.  A published study fed multiple sclerosis patients cow myelin (which contains both myelin basic protein and proteolipid protein) and examined whether this affected immune response to myelin (Hafler, DA et al. Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis. Ann NY Acad Sci 1997 Dec 19;835:120-31).

The investigators took blood from 34 patients with relapse remitting multiple sclerosis that were either fed cow myelin (17 patients) or not fed it (17 control patients) and generated T cell lines that recognized either myelin basic protein (MBP), proteolipid protein (PLP), or tetanus toxin (TT). 

A profound increase in the number of cells secreting the antiinflammatory cytokine TGF-b on stimulation with MBP or PLP was seen in patients who ate the cow myelin as opposed to controls.  Interestingly, there was no increase in production of the inflammatory cytokine interferon gamma, nor were there alterations in response to tetanus toxin. 

These data suggest that at least at an immunological level administration of oral cow myelin is helpful in patients with multiple sclerosis.  The question now because, can one increase therapeutic effects by combining the cow myelin with something like lithium, or with fat stem cells?  Furthermore, clinically used drugs such as metformin, which may conceptually increase Treg generation by suppressing IL-17 may be useful to expand the overall tolerogenic profile of oral tolerance induction.

We previously discussed the concept of DNA vaccination for antigen-specific modulation of the immune system in conditions of autoimmunity such as multiple sclerosis.  In essence, it appears that DNA-based administration of the same proteins that are targets of the immune system during autoimmunity seem to suppress the immune response in a specific manner.  This is different than other immune modulators such as anti-CD25 antibody or Tysabri which suppresses in a non-specific manner.

A published Phase I/II trial of BHT-3009, Bayhill Therapeutics DNA vaccine for myelin basic protein in 30 patients with either secondary progressive or relapse-remitting multiple sclerosis was performed in which antigen-specific immune modulation was seen, and safety of the vaccine was demonstrated.  Here we will discuss a larger trial by the same group that was recently published (Garren et al. Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann Neurol 2008 May;63(5):611-20).

This trial was much larger than the previous trial (267 patients), and was limited to patients with relapse-remitting multiple sclerosis.  The patients were randomized to receive either placebo, or two doses (0.5 mg and 1.5 mg) of the DNA vaccine (BHT-3009).  DNA vaccination was performed intramuscularly at the timepoints of initiation, after 2 weeks, after 4 weeks and subsequently given for every month until the 44th week. 

The data demonstrated that in comparison to patients receiving placebo there were no positive effects of the 1.5 mg dose.  In contrast, the 0.5 mg dose caused a 50-61% reduction in new lesion formation as detected by MRI and profound reduction of anti-myelin antibodies.

These data support further expansion of the DNA vaccine approach into phase III clinical trials.  These data, as well as other antigen-specific tolerogenic vaccines may be one of the reasons why entered a $350 million deal with Genetech.

The immune system self-regulates itself through many mechanisms, for example, thymic deletion of autoreactive cells, the need for co-stimulation for activation of T cells, and also through T regulatory (Treg) cells that recognize proteins that belong to the body and stop other T cells from attacking these proteins.  Another way in which activated T cells control themselves is by increasing expression of a molecule called CTLA-4.

This molecule works through several means.  One is outcompeting CD28 for access to CD80 and CD86 on the antigen presenting cell, the other is by sending a suppressive signal to the antigen presenting cell.

To activate a T cell, generally speaking, one requires 2 main signals, the T cell receptor (TCR) has to recognize a major histocompatibility complex (MHC) molecule that has a peptide inside of it.  If the TCR appropriately “fits” into the MHC-peptide complex, then the TCR sends a signal into the T cell.  However this first signal is not enough to activate the T cell.  The T cell requires another signal from the antigen presenting cell.  This second signal, also called costimulatory signal, is usually in the form of CD80 and/or CD86 from the antigen presenting cell, which both bind to CD28 on the T cell.  The activation of CD28 and the TCR on the T cell results in T cell activation.  When only the TCR is activated without CD28, then the T cell either goes into a state of prolonged unresponsiveness (called anergy), or in some situations actually can start expressing immune suppressive properties.  CTLA4 is turned on by the T cell after the T cell is activated. CTLA4 binds with much higher affinity to CD80 and CD86 than does CD28.  Therefore, after T cell activation, the T cell can “turn itself off” by expressing CTLA4.

Studies have demonstrated that activated T cells expressing CTLA4 can bind to dendritic cells (most potent antigen presenting cells), and that the CTLA4 on the activated T cell sents a negative signal to the dendritic cell, inducing the dendritic cell to secrete immune suppressive proteins and upregulate expression of the enzyme indolamine 2,3 deoxygenase (IDO) which in turn suppresses other T cells.

Interestingly CTLA4 is expressed not only by activated T cells but also by Treg cells.

Given the ability of CTLA4 to suppress immune responses via at least 2 mechanisms (more are known), scientists have tried to use CTLA4 therapeutically.  To make a soluble form of CTLA4 that can be administered, a pharmaceutical form has been developed by fusing the protein CTLA4 with the immunoglobulin domain of IgG, to make a chimeric molecule called CTLA4-Ig.  Currently CTLA4-Ig is sold by Bristol Myers Squibb under the name Abatacept (Orencia) for the treatment of rheumatoid arthritis that is nonresponsive to TNF-alpha inhibitors such as Remicade.

Given the immune modulatory properties of CTLA4-Ig, one question is whether it may inhibit suppress autoimmune responses in patients with multiple sclerosis.  A recent study (Viglietta et al. CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial. Neurology 2008 Sep 16;71(12):917-24) assessed this in a small clinical trial.

The investigators performed a Phase I trial, meaning that the primary endpoint was toxicity and ability to identify therapeutic dose for subsequent Phase II investigations.  A total of 20 patients with relapse remitting multiple sclerosis were treated with intravenous infusions of CTLA4-Ig and monitored for 3 months. 

CTLA4-Ig administration correlated with suppression of interferon gamma production and proliferation in response to myelin basic protein ex vivo.  The treatment elicited no serious treatment associated adverse events, although some mild adverse events were reported.

This study demonstrated feasibility of CTLA4-Ig administration in relapse remitting multiple sclerosis, and provides support for further Phase II trials.

Unfortunately CTLA4-Ig is still a non-specific immune suppressant in that it globally inhibits activation of T cells and theoretically could predispose to infections.  One important question is whether the CTLA4-Ig administration may help to “reprogram” the immune system so as to promote eventual tolerance to the myelin antigens while leaving immunity to extracorporal antigens intact. 

A possible approach would be to use CTLA4-Ig in combination with antigen-specific approaches such as vaccination with autoreactive T cells.  Additionally, it will be important to assess the effects of CTLA4-Ig on Treg cells.  For example, we know that interferon beta, which induces therapeutic effects in multiple sclerosis stimulates Treg activity.  We also know from animal studies (Salomon et al.  B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. 2000 Apr;12(4):431-40) that administration of CTLA4-Ig can actually block Treg generation, so if interferon beta works through Treg generation, the combination may not work.

We previously discussed a paper demonstrating augmentation of T regulatory cell (Treg) activity in patients with relapse-remitting multiple sclerosis after initiation of interferon beta therapy.  The possibility that one can increase activity of these cells whose physiological function is to prevent autoimmunity is very intriguing.  Therefore, we thought it may be worthwhile to see what else has been published on Treg cells in the area of multiple sclerosis patients, so we will talk about a publication (Viglietta et al. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004 Apr 5;199(7):971-9) from Dr. David Hafler’s group at Harvard investigating differences between healthy volunteers and patients with multiple sclerosis in terms of Treg activity. 

Before we begin discussing the paper, let us ask ourselves, how would one measure Treg activity?  If you think about it, it is actually very difficult if done in the most pure fashion.  What we mean is that theoretically, the cells that are protecting the body from immunological attack would have a specific receptor, a specific T cell receptor (TCR) that recognizes the myelin basic protein and that stops the “conventional” T cells, or “T effector cells” which also are recognizing the myelin basic protein from attacking the myelin sheath.  In other words, quantification of the suppressive activity of all the Tregs in the body may or may not be the best way to assess whether the Tregs are working or not.  The most important Tregs are the ones that inhibit the attack on the myelin, the other Tregs, that prevent attack against, say, collagen II (antigen in rheumatoid arthritis), or GAD65 (antigen in type I diabetes) are not important for the situation of multiple sclerosis.

Unfortunately, we dont know all of the antigens that the T cells are attacking in multiple sclerosis, and it is difficult to measure only the Treg cells that are specific for antigens that we do know.  When one is trying to quantify effector cells, there is something called “tetramer technology” in which peptides are bound to labelled proteins that resemble the MHC complex, and flowcytometry can be used for assessment.  I wonder why we dont really see this being done with quantification of Treg cells.  My guess is that they are found in much smaller numbers than the effector cells and thats why its difficult.  Just to give you an idea, Treg cells comprise approximately 5% of the CD4 population, with the other 95% being conventional T cells, or T effector cells.

So in the publication, assessment of Treg function was performed by adding increasing numbers of Treg cells (defined as CD4+ CD25+) to a fixed number of T effector cells (CD4+ CD25+) and providing an activation signal (anti-CD3 monoclonal antibody) that nonspecifically activates the T cell receptor of both the Treg and the T effector cells.  Activation of the cells can easily be measured by the rate at which the cells divide, as well as cytokines that they make.

So one would expect that if only T effector cells were mixed with the anti-CD3 antibody, there would be proliferation, and with the increasing number of Treg cells added to the mix, there would be a suppression of the proliferation.  As seen in the figure below, with increasing number of Treg cells there is an increase in suppression.  Most interestingly the addition of Tregs from MS patients did not seem to suppress the anti-CD3 stimulated proliferation as well as the Tregs derived from healthy volunteers.  The data is representative of a total of 21 healthy controls and 15 patients with multiple sclerosis.

These data seem to suggest that Treg cell function is compromised in patients with multiple sclerosis.  The question is, what could be compromising it?  There are many things that inhibit function of Treg, or example, ligation of the protein GITR-ligand has been demonstrated to abolish Treg activity.  Interleukin-6 in some situations has also been demonstrated to inhibit Treg activity.  Additionally, inflammatory stimuli such as activation of various toll like receptors has also been associated with suppression of activity.  However, none of these factors really come to mind when one thinks of multiple sclerosis patients. 

One other question that is posed by these data is whether multiple sclerosis patients would be predisposed to other autoimmune diseases?  Clinically multiple sclerosis seems to present as a distinct entity.  So if the immune attack is only against nervous system tissue, specifically the myelin sheath, why would ALL the Tregs seem to have deficient function? 

Another question is whether the lack of Treg activity is a cause of disease or whether it is a symptom.  For example, it may be that the intial immune reaction against the myelin sheath may stimulate systemic changes and inflammation that could in turn somehow modulate Treg activity.  In fact, systemic inflammatory mediators such as serum amyloid A protein is actually increased in patients with multiple sclerosis (Boylan et al. Interferon-beta1a administration results in a transient increase of serum amyloid A protein and C-reactive protein: comparison with other markers of inflammation. Immunol Lett 2001 Jan 15;75(3):191-7). 

The ability of mesenchymal stem cells to reduce systemic inflammation is best demonstrated in clinical studies of patients with steroid refractory GVHD which seem to respond after administration of non-matched bone marrow derived MSC (www.osiris.com).  It therefore makes sense to see some of the animal and early human data demonstrating activity of mesenchymal stem cells in multiple sclerosis.

Autoimmunity, such as multiple sclerosis, is characterized by the immune system attacking components of the body.  Normally the body has numerous mechanisms of protecting itself from this, which we have previously discussed.  One way that the immune system “self regulates” itself is by a special type of T cell, called that T regulatory (Treg) cell.  The T cell receptor (TCR) of Treg cells is usually activated by recognition of proteins of the body.  This is an interesting point.  “Normal” T cells are usually turned on when their T cell receptor recognizes parts of proteins (called peptides) that are found on components that do not belong in the body.  Unfortunately in situations such as multiple sclerosis, rheumatoid arthritis, or Type 1 Diabetes, the T cells that are suppose to be activated by foreign peptides are activated by peptides that belong to the body (in multiple sclerosis the T cells are attacking components of the myelin basic protein which acts as an insulator around axons of the nerves).  The Treg cells, which recognize myelin basic protein are activated by the myelin basic protein components as well as by the presence of the conventional T cells being activitated.  What occurs is that the Treg cells attempt to suppress the destruction of the myelin by the normal T cells, through producing various chemical mediators, called cytokines, that suppress the effects of the conventional T cells.

So to try to state it in another way:  Conventional T cells activate the immune response and cause damage.  In the healthy situation, the conventional T cells cause damage to bacteria, virus infected cells, and cancer cells.  In the healthy situation Treg cells act as a protective mechanism so that in the cases that the conventional T cells start attacking components of the body, the Treg cells then inhibit the conventional T cells from doing this.  So another way of thinking about it is that the Treg cells are a “safety backup” so that the body does not attack itself.

So the question then becomes, what is going on in autoimmunity in general and specifically in conditions such as multiple sclerosis?  Are these Treg cells not doing their job properly?

There is a recent paper that was published (Korporal et al. Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells. Arch Neurol. 2008 Nov;65(11):1434-9) assessing Treg activity in 18 healthy volunteers and 20 patients with relapse-remitting multiple sclerosis. 

When comparing Treg activity between the healthy volunteers and the relapse remitting multiple sclerosis patients they found that ability of Treg to suppress immune response was deficient in the multiple sclerosis patients as compared to controls.

But the investigators then took the study a step further.  They assessed the Treg activity in patients before and after starting to take interferon beta therapy (Avonex is a type of interferon beta).  They found that both at 3 and 6 months after administration of interferon beta the suppressive activity of the Treg was restored to normal levels.  See figure below. 

Restoration of Treg Activity after Interferon beta Therapy

Given that mesenchymal stem cells have been demonstrated to induce Treg activity, and that adipose stem cells actually have high concentrations of Treg, two interesting questions arise.  Firstly, can interferon beta therapy synergize with stem cells?  Secondly, can autologous adipose stem cell therapy serve as a substitute for interferon beta therapy? 

Other thoughts come to mind as well, such as, can if indeed Vitamin D is associated with Treg activity, would it synergize or antagonize the effects of interferon beta on the Treg and actually on the clinical situation?

Laquinimod (originally called ABR-215062) is a small molecule, orally active, drug being developed as a treatment for multiple sclerosis.  Laquinimod is chemically related to roquinimex, an immune modulator that was previously used in treatment of multiple sclerosis patients, but development was discontinued due to side effects.  Animal studies in the experimental allergic encephalomyelitis (EAE) model demonstrated that laquinimod is approximately 20 times more active at inhibiting autoimmunity as compared to roquinimex (Brunmark et al. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2002 Sep;130(1-2):163-72).  It is believed that both laquinimod and roquinimex work via inducing a Th1 to Th2 shift.

The results of a double-blind, placebo control trial of laquinimod were published (Comi et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008 Jun 21;371(9630):2085-92).

The investigators treated 98 patients with laquinimod at 0.3 mg/day, 106 patients with 0.6 mg/day, and assigned 102 patients to the placebo group.  All patients were diagnosed with relapse remitting multiple sclerosis.

Assessment of efficacy was performed at 4 weeks before the study, at baseline, and every month from week 12 to 36. 

While the group that recieved 0.3 mg per day of laquinimod did not have improvements over placebo in terms of gadolinium enhancing lesions, the 0.6 mg per day group had a reduction of 40.4% over placebo.

Overall both doses of laquinimod were well tolerated, however one patient developed a liver abnormality which was successfully treated.

Plasma exchange (also called plasmapheresis) is the procedure in which blood is taken from the patient, the plasma is removed and replaced with donor plasma (or sometimes plasma replacements such as albumin), and reintroduced into the body with the original cellular component.

The aim of the procedure is to deplete the blood of various immunological factors, such as antibodies, that may be associated with pathology, or causing of the disease process.  Obviously this is a short-term solution since antibodies are made by B cells and the original B cells that are making putatively harmful antibodies will still be in the patient after the plasmapheresis is complete.  However it may be that the plasmapheresis gives the immune system time to “re-adjust itself”.  An extreme example of the immune system re-adjusting itself is in the clinical trials where they patient’s hematopoietic (blood making) stem cells are extracted, the patient’s immune system is destroyed on purpose, and then the hematopoietic stem cells are placed back into the patient to create a “re-adjusted” immune system that hopefully will not be attacking the myelin sheath anymore.  Obviously this process has many possible side effects and at least theoretically, it seems more attractive to use your own fat derived stem cells for multiple sclerosis. 

In any case, plasma exchange offers the possibility of removing some of the pathological components so that the immune system may try to “self-regulate” itself.  How could this be?  One possibility of this is through giving T regulatory cells a chance by reducing the inflammation-creating cytokines and antibodies found in the plasma of multiple sclerosis patients.  On the other hand, the actual effector cells in multiple sclerosis are the CD4 T cells, which activate macrophages and myeloid cells to infiltrate the central nervious system, so would removal of antibodies and soluble components really have a significant impact?

The area of plasma exchange for multiple sclerosis appears to be rather controversial.  On its website, the National MS Society states: “It is not clear whether plasmapheresis is of benefit in the short- or long-term treatment of MS, and its use in MS remains controversial.”

We write about plasma exchange for multiple sclerosis today because a recent paper was published (Trebst et al. Plasma Exchange Therapy in Steroid-Unresponsive Relapses in Patients with Multiple Sclerosis. Blood Purif. 2009 Jun 11;28(2):108-115) in which 20 patients who were unresponsive to steroids were reported upon. 

The investigators from the Department of Neurology, Medical School Hannover, Hannover, Germany, reported ”a marked-to-moderate clinical response with clear gain of function in 76% of patients with uni- or bilateral optic neuritis and in 87.5% of patients with relapses other than optic neuritis was observed.”

The concluded that “Plasma exchange is an effective and well tolerated therapeutic option for steroid-unresponsive MS relapses.”

It will be interesting to elucidate the immunological mechanisms by which plasma exchange may mediate its effects, and if it may be incorporated into other immune modulatory therapies.  Such a simple incorporation could be the combination of plasma exchange and antigen-specific immunization to achieve tolerance.  We previously discussed here that immunization in the presence of inflammation or “danger” is often associated with immune activation, whereas introduction of antigen in absence of inflammation can be associated with tolerance.  Therefore by “washing the body” of inflammatory agents, one may achieve even better effects with agents such as BioMS’s MBP8298 product or Bayhill Therapeutic’s myelin basic protein DNA vaccine called BHT-3009. 

It is possible that in the future be combined with agents that increase existing nerve condition such as fampridine and of course mesenchymal stem cells.

As we discussed here on StemNow.com, the possibility of antigen-specific tolerance for multiple sclerosis is, along with regenerative medicine, the most promising area of research in this field. 

Clinical trials have previously tried to induce tolerance in multiple sclerosis by selectively inducing immune response against the autoreactive T cells, with some degree of effect. 

The current clinical trial that we will discuss here uses immunization with a DNA vaccine encoding myelin basic protein to induce antigen-specific tolerance, or inhibition of immunity.   It was published as a collaboration between the company Bayhill Therapeutics, and several academic centers (Bar-Or et al. Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Arch Neurol 2007 Oct;64(10):1407-15). 

Since myelin basic protein is what the immune system is attacking in multiple sclerosis, or at least one of the main targets, the idea was that if myelin basic protein could be administered intramuscularly, or better said, expressed intramuscularly, then through the immune system may actually be suppressed in response to it.  Below is a picture of the plasmid that was used for injection. 

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This study is interesting because it is, to our knowledge, the first time that DNA vaccination was used for induction of immunological tolerance in patients in an antigen-specific manner.  Unfortunately, the lack of actual efficacy in MRI lesion size, or even lack of symptomological improvement (it was not discussed), suggests that numerous other modifications, or at least large sample sizes, need to be performed to see an effect.

On a positive note, one of the interesting features of this study was that even though the antigen myelin basic protein was administered as a “tolerogen”, inhibition of immune responses against other autoantigens, such as PLP.  This suggests that the immune system may be somehow “re-educating itself”.  We proposed the concept of “epitope spreading” in the context of immune regulation many years ago, and this may be an excellent example.

Given that autologous stromal vascular fraction contains antiinflammatory cells in addition to regenerative mesenchymal stem cells, it may be worthwhile to see whether adipose non-expanded stem cell therapy affects epitope spreading both from the pathogenic and regulatory perspective.

We at StemNow.com believe that it is important not only to know what the most recent, cutting edge, therapies and ideas are in the field of multiple sclerosis, but also to have knowledge of the medical history of how we got to where we are today.  So we will discuss some older work here.

A paper from 1976 (Ring et al. Pilot study with antilymphocyte globulin in the treatment of multiple sclerosis. Postgrad Med J. 1976;52(5 Suppl):123-30) describes a clinical trial using antilymphocytic globulin for treatment of patients who have not been previously responsive to azathioprine or steroids.

In contrast to relatively more specific methods of blocking T cells, such as Daclizumab which blocks activated T cells (and maybe but hopefully not T regulatory cells), antilymphocyte globulin inhibits all T cells, it is made by immunizing horses or more often, rabbits, with human lymphocytes, and then collecting the antibody fraction and injecting it into the human in need of treatment. 

In the clinical trial, a total of 20 patients were treated. 

7 patients recieved antilymphocyte globulin alone

5 patients had thoracic duct drainage.  The thoracic duct is what collects the majority of the lymphatic fluid and drains it into the blood stream via the left subclavian vein.  Presumably by draining the thoracic duct one would reduce immune reactivity.

8 patients recieved antilymphocyte globulin together with the procedure of thoracic duct drainage.

In the patients receiving antilymphocyte globulin alone 4/7 had remarkable improvement in symptomology. 

In the patients recieving combination of antilymphocyte globulin and thoracic duct drainage, severe allergic reactions developed, which did not allow for complete dose escalation of the antilymphocyte globulin.  However 4 of the 8 patients had improvements that lasted for several years.

Patients receiving thoracic drainage alone had no improvements.

Antilymphocyte globulin is not used today, or at least not in widespread use, because of the various allergic reactions associated with administration of relatively undefined antibodies from another species into humans.  There is, however, anti-thymocyte globulin, which is commercially available from Genzyme (called Thymoglobulin, raised in rabbits against human thymocytes), and Pfizer (called Atgam, raised in horses against human thymocytes. Both of these agents are only approved for treatment of transplant rejection, however clinical trials have been performed in multiple sclerosis.

The problem with this sort of global suppression of the immune system is the possibility of opportunistic infections while the immune system is not functioning.

Avonex (interferon beta 1a) is approved for relapse remitting multiple sclerosis based on studies demonstrating reduction in relapse rates and improvement in EDSS scores.  A recent clinical trial sought to determine whether Avonex would work better with the steroid methylprednisolone and the chemotherapeutic agent methotrexate (Cohen et al. Results of the AvonexCombination Trial (ACT) in relapsing-remitting MS. Neurology 2009 Feb 10;72(6):535-41).

The study comprised of 313 patients with relapse remitting multiple sclerosis having an EDSS score between 0-5.5 and one or more relapses or gadolinium-enhancing lesions on MRI while taking Avonex alone in the past year. 

Patients were randomized to receive either Avonex alone with placebo, or Avonex with methotrexate, or Avonex with methotrexate and methylprednisolone. 

The main goal of the study was to assess whether the intervention would affect the rate of new or bigger lesions at the one year timepoint after treatment as compared to before trial initiation.  

Adverse effects of the combinations were not substantially amplified, however no statistically significant improvements or patient benefits were reported using the trial assessment parameters.  Interestingly, the patients recieving steroids had a reduced number of antibodies to the Avonex (most likely due to non-specific immune suppression).

In conclusion, this trial did not demonstrate any reason for combining non-specific immune modulators in terms of enhancing efficacy against multiple sclerosis. 

It will be interesting to see trials in which immune modulators such as Avonex, which are known at least in part to influence T regulatory cells, are combined with regenerative approaches such as administration of mesenchymal stem cells.