November 17, 2010 by

Why should mesenchymal stem cells (MSCs) cure autoimmune diseases?

Uccelli A, Prockop DJ. Curr Opin Immunol. 2010 Dec;22(6):768-74. Epub

As many readers of Cellmedicine News most likely realize, the concept of stem cell therapy is still relatively controversial. Despite the fact that clinical trials have demonstrated therapeutic signals that various stem cells are useful in treatment of diseases ranging from multiple sclerosis, to type 1 diabetes, to lupus, people, especially uninformed people in the public media, still treat the field of stem cell therapy of autoimmunity as something “controversial”. This is why we were pleasantly surprised to read the recently published paper of Dr. Darwin Prockop, from Tulane University, which actually used the word “cure” in the title.

In the paper animal and clinical data is reviewed describing effects of a particular type of stem cell, the mesenchymal stem cell, in treatment of autoimmunity. Mesenchymal stem cells were originally found in the bone marrow, and subsequently discovered in other tissues. These cells are capable of generating new tissues, but perhaps more importantly, have been demonstrated to be potent secretors of various growth factors and to modulate the immune system. We discuss some of these points on our youtube channel http://www.youtube.com/watch?v=rEJfGu29Rg8

The paper focuses much attention on multiple sclerosis and the detailed animal experimentation in the mouse model of this disease, experimental allergic encephalomyelitis (EAE), which has provided some detailed clues about how these cells may work. Induction of EAE is typically performed by immunizing mice with peptides or proteins that are found in the myelin. This induces an immune response that attacks the myelin and results in a progressive degeneration of the myelin sheath, as well as loss of function which mimics the human disease. Many of the studies discussed in the paper support the general hypothesis that the mesenchymal stem cells are acting to “reprogram” the immune system in order to stop the immune attack against the myelin but preserve other components of the immune system. The authors then extrapolate how these immunomodulatory mechanisms may have activity against other types of autoimmune conditions.

Currently there are several clinical trials using mesenchymal stem cells for autoimmune conditions. These may be found at www.clinicaltrials.gov if you search the words “stem cells” and “autoimmune.”

Filed Under: Autoimmune Disease, News, Stem Cell Research Tagged With: , , ,
September 2, 2010 by

Beike Biotechnology Reports on 114 Patients Treated with Novel Cord Blood Stem Cell Protocol

New Approach Opens Door to Expanded Uses of Cord Blood Stem Cells
Beike Biotechnology Press Release

Beiki Biotechnology and Medistem Inc (MEDS.PK) report positive safety data in 114 patients with neurological conditions treated using Beiki’s proprietary cord blood stem cell transplantation protocol. In the peer-reviewed paper “Safety evaluation of allogeneic umbilical cord blood mononuclear cell therapy for degenerative conditions” available at http://www.translational-medicine.com/content/pdf/1479-5876-8-75.pdf ., a team of researchers from Bieke Biotechnology, Medistem Inc, University of Western Ontario, Canada, and University of California, San Diego, describe biochemical, hematological, immunological, and general safety profile of patients with neurological diseases who were observed between 1 month to 4 years after treatment. No serious treatment associated adverse effects were observed. The current report aims to serve as an “expanded Phase I” study, with efficacy data to be published in a subsequent paper.

“Although it is well understood in the scientific community that cord blood stem cells are useful in treatment of terrible degenerative diseases ranging from heart failure, to stroke, to ALS, to multiple sclerosis, the fact that under current protocols immune suppressants are necessary, limits the use of cord blood to treatment of leukemias in the United States and Western Europe.” Said Dr. Hu CEO of Beike . He continued “This is the first time someone has demonstrated on such a large patient population feasibility of non-matched, non-immune suppressed, cord blood stem cell transplantation.”

The current medical dogma states that patients receiving cord blood transplants need to be immune suppressed, otherwise the cord blood will cause a devastating condition termed graft versus host. Due to the potentially lethal effects of immune suppression, cord blood stem cells are not used on a widespread basis, with the exception of treating aggressive leukemias. The technology developed by Beike allows the use of cord blood stem cells without immune suppression, thus opening up the use of this procedure to a much wider patient population.

“It is our honor to collaborate with Beike on this seminal publication. We at Medistem have been developing the concept of “universal donor endometrial regenerative cells”, which are a new stem cell that does not require tissue matching. The fact that Beike has been able to demonstrate safety of transplant by manipulating an established stem cell source is a substantial advancement for the field.” Said Thomas Ichim, CEO of Medistem Inc. “Concretely speaking, the findings of the current paper could open up the use of cord blood for non-hematological diseases, something that to date has not been performed on a wide-spread basis.”

Filed Under: Cord Blood Stem Cells, News, Stem Cell Research Tagged With: , , , , ,
August 2, 2010 by

Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study.

Liang et al. Ann Rheum Dis. 2010 Aug;69(8):1423-9.

Mesenchymal stem cells are unique in that on the one hand they are capable of differentiating into a variety of tissues, but on the other hand they also are potently anti-inflammatory and immune modulatory.

Evidence of immune modulation comes from studies that show mesenchymal stem cells: a) directly suppress ongoing mixed lymphocyte reaction; b) produce immune suppressive cytokines such as IL-10; c) produce immune suppressive enzymes such as indolamine 2,3 deoxygenase; d) inhibit natural killer and CD8 cytotoxic T cell activity; e) inhibit dendritic cell maturation; and f) stimulate production of T regulatory cells.

Animal studies covered on our youtube channel www.youtube.com/cellmedicine have shown that mesenchymal stem cells inhibit collagen induced arthritis and experimental allergic encephalomyelitis, which represent human rheumatoid arthritis and multiple sclerosis, respectively.

Since these cells are such potent immune modulators, they have been used with some success in the treatment of immunological diseases such as graft versus host disease (GVHD). Medistem and Cellmedicine have previously used fat derived stem cells, which contain high concentrations of mesenchymal stem cells, in order to treat rheumatoid arthritis. In the current paper mesenchymal stem cells from the bone marrow where used to treat the autoimmune disease systemic lupus erythematosus.

Scientists at the Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, in Nanjing, China, reported a clinical trial of allogeneic (universal donor) mesenchymal stem cells in the treatment of patients with treatment-refractory systemic lupus erythematosus (SLE).

Fifteen patients with SLE who did not respond to conventional treatments where administered bone marrow derived mesenchymal stem cells isolated from allogeneic donors. No chemotherapy or immune suppression was used. Administration of stem cells was performed intravenously.

Mean patient follow up was 17.2+/-9.5 months with 13 patients have been followed for more than 12 months. 15/15 patients presented with clinical improvements subsequent to stem cell therapy. At 12-month follow-up, SLEDAI scores dropped from 12.2+/-3.3 to 3.2+/-2.8 and proteinuria decreased from 2505.0+/-1323.9 to 858.0+/-800.7 mg/24 h. At 1-year follow-up in 13 patients, 2 had a relapse of proteinuria, while the other 11 continue to have decreased disease activity on minimal treatment. Anti-dsDNA levels decreased. Improvement in glomerular filtration rate was noted in two patients in which formal testing was performed. Non-renal-related manifestations also improved significantly. No serious adverse events were reported.

This study demonstrated that mesenchymal stem cells are capable of not only inhibiting the pathological processes in SLE (eg production of anti-dsDNA antibodies) but also reversing renal damage that has occurred as a result of the disease process. The fact that some of the patients relapsed may mean that there is a rationale for multiple administration of mesenchymal stem cells.

Filed Under: Adult Stem Cells, Lupus, News, Stem Cell Research Tagged With: , , , , ,
August 1, 2010 by

Pluripotent stem cell-derived natural killer cells for cancer therapy.

Knorr et al. Transl Res. 2010 Sep;156(3):147-154. Epub

Immune therapy of cancer is an exciting prospect given the possibility of treating cancer without the side effects associated with conventional treatments such as chemotherapy or radiotherapy. Additionally, the use of the immune system to target tumors offers the possibility of eradicating micrometastasis, which often cannot be treated by conventional means.

Early work in the immunotherapy of cancer involved taking out patient lymphocytes that were infiltrating the tumor, expanding them outside of the body, and subsequently re-injecting them with the hope that expanded numbers of tumor-specific killer cells would destroy the tumor. Unfortunately this approach was very expensive and did not yield positive results to justify the complexity and expense of the procedure. One possible reason for the failure of this approach is that the cells used where already “old” and “exhausted”. In other words, previous encounters of the T cells with cancer antigens seems to have programmed them so as to inhibit ability to mount a proper immune response.

The use of natural killer cells as an alternative to T cells was considered. These cells, called lymphokine activated killers (LAK) displayed specific ability to kill tumors and were more effective than T cells alone. Unfortunately this approach too also required substantial manipulation of the cells outside of the body and was not practical.

In a recent paper, the group of Knorr et al discussed how to use stem cells to solve the problem of generating anti-cancer immune cells out of the body. They discuss how they have successfully used embryonic stem cells to generate “universal donor” natural killer cells. This approach is highly promising since NK cells do not need to be matched with the recipient in order to mediate anti-cancer activity. Additionally, since the cells are generated “brand new” in the laboratory, the problem of “exhaustion” is no longer relevant. Unfortunately there are still several obstacles to overcome such as the potential of embryonic stem cells forming leukemias/tumors, and the possibility of host anti-graft responses.

The paper also describes the future possibility of using inducible pluripotent stem (iPS) cells as a method of generating autologous T cells with any given TCR specificity.

Filed Under: Cancer, News, Stem Cell Research Tagged With: , , ,
February 28, 2010 by

Ahmedabad-based institutes get patent to use stem cells in kidney transplant

According to an article IndianExpress.com, an international
patent has been issued to the G R Doshi K M Mehta Institute of Kidney Diseases
and Research Centre (IKDRC) and Dr HL Trivedi Institute of Transplantation
Sciences (ITS) from Ahmedabad, Indian for utilization of stem cells in treatment
of patients having undergone kidney transplantation.  Given that we could not
find a patent number written in the article, as well as the fact that
"International Patents" do not exist, we presume the authors meant a provisional
patent having international priority under Paris Convention, or a Patent
Cooperation Treaty (PCT) application. 

The subject matter discussed is the use of stem cells to
circumvent the need for immune suppression during transplantation.  While immune
suppressants such as cyclosporine, rapamycin, and FK-506 have saved many lives
by making transplantation possible, they have numerous side effects associated
with their long-term use.  These include increased risk of cancer, higher number
of bacterial/viral infections, and possibility of kidney failure.  The work
discussed in the article uses the ability of stem cells to "immune modulate" and
therefore inhibit rejection.  A video describing stem cell mediated immune
modulation may be seen at this link

http://www.youtube.com/watch?v=ECi2uBSSQg8.  

Dr Aruna Vanikar, Head of Pathology, Lab Medicine,
Transfusion Services and Immuno hematology department, IKDRC-ITS, who according
to the article recently received the patent, stated, "We have been working on
the use of stem cells since 1998. The study involved several phases. When a
patient undergoes kidney transplant, he/she might face difficulties, including
complete rejection. To suppress that, several drugs are used…Sometimes, the body
also reacts to high dosage of drugs. With this patent, patients will not have
any such complications. The stem cells would comprise mesenchymal cells
generated from the donors’ fat, and haematopoetic stem cells taken from donors’
bone marrow and blood. These cells are infused in the recipients’ liver, as it
is considered the most tolerogenic organ of the body."

While the article did not provide technical details, we
found on

www.pubmed.com some of Dr. Vanikar’s work.  A recent publication: Effect of
co-transplantation of mesenchymal stem cells and hematopoietic stem cells as
compared to hematopoietic stem cell transplantation alone in renal
transplantation to achieve donor hypo-responsiveness. In the journal Jan 19th
edition of the International Urology and Nephrology Journal described the
reduction of immune suppressant dosage by administration of bone marrow and fat
derived stem cells.  Another paper from the same group described the reduction
of immune suppressant dose by a similar stem cell protocol, termed the
"Ahmedabad tolerance induction protocol".  It will be interesting to see if
these early clinical results can be translated into Phase III placebo controlled
trials.  Commenting on the "tolerance induction protocol" Dr Aruna Vanikar said:
"With modification in Ahmedabad tolerance induction protocols for
transplantation without conventional immunosuppression, the results are
rewarding. Secondly, the incidences of acute and chronic rejection and
recurrence of basic disease have decreased."

Filed Under: Kidney and Lung, News, Stem Cell Research Tagged With: , , , ,
February 24, 2010 by

Stem Cells for HIV?

HIV infection causes its devastating effects on patients by
destruction of the CD4 T helper cell and macrophage component of the immune
system.  Entry of the virus into these cells occurs via binding to the molecules
CD4 and CCR5.  Interestingly a group of patients who appear to be resistant to
HIV infection have a mutation in the CCR5 protein.  Studies conducted on these
patients have demonstrated that the mutation in CCR5 results in resistance to
infection, while other components of the immune system of these patients are
intact.  Thus one possible method of treating HIV would be if somehow one could
induce the CCR5 mutation that is protective from HIV into the immune cells of
patients.  It is very difficult to selectively mutate established immune cells,
however, one possibility would be if one could induce such a mutation in stem
cells, and then administer the stem cells to the patient so that they
"differentiate" into immune cells.

Scientists from the Department of Microbiology, Immunology
and Molecular Genetics, at the David Geffen School of Medicine, University of
California at Los Angeles have started figuring methods of doing this. 
Specifically, a new technology called "RNA Interference" was used to selectively
block expression of the CCR5 gene on stem cells.  RNA interference is a process
that is normally used by mammalian cells to protect themselves against viruses. 
Specifically, RNA is found only as a single strand in mammalian cells.  Double
stranded RNA is found only in viruses.  When a mammalian cell recognizes double
stranded RNA it believes that a viral infection is occurring and two processes
are triggered.  The first is gene-nonspecific.  Regardless of what is coded in
the double stranded RNA, the cell starts to produce the protein interferon,
which blocks other cells from being infected, as well, the cell alters various
metabolic activities and enters a quiescent state.  The second process is
gene-specific, in that the cell will destroy any other RNA that resembles what
is encoded in the double strand.  While the first effect is useful for
inhibition of viral infections, it is non-specific and causes general toxicity
when administered at high enough levels to people or animals in order to elicit
an effect.  Thus a Nobel Prize was awarded in 2006 to Fire and Mello when they
discovered that by administering pieces of double stranded RNA shorter than 21
nucleotides, the selective gene-silencing effect could be induced in absence of
the non-selective "interferon effect".

In their recent paper, Liang et al used RNA interference to
block expression of the CCR5 gene on stem cells that are capable of giving rise
to both CD4 T cells, as well as macrophages.  They demonstrated that
gene-blockade was passed on to the progeny of the stem cell, and that the newly
generated cells were resistant to HIV infection in vitro.

In contrast to using stem cells for hematopoietic
transplantation, in which depletion of the original recipient cells is required,
the use of genetically engineered stem cells for treatment of HIV would not
require such myeloablation since the HIV infection will naturally be killing the
non-manipulated cells.

Filed Under: HIV, News, Stem Cell Research Tagged With: , , , , ,