Faustman and Faustman-related research

[danismom79]

I wanted to start this thread to share studies by Dr. Denise Faustman (http://www.faustmanlab.com), as well as studies that are relevant to her method. For those who don't know, Dr. Faustman cured end-stage non-obese diabetic (NOD) mice by injecting them with a compound that stopped the autoimmune attack, leading to the restoration of insulin production (articles below).

I'd like this to be a running thread where people can post other studies.

Possible topics/search terms:
BCG vaccination and type 1 diabetes
CD8+ T-cells and autoimmunity
NOD mice
TNF-alpha

It would be great if anyone who has access to scientific journals could post the full articles.

I'll start.

I have this article in PDF
Shohta Kodama, Willem Kuhtreiber, Satoshi Fujimura, Elizabeth A. Dale, Denise L. Faustman. 2003. "Islet Regeneration During the Reversal of Autoimmune Diabetes in NOD Mice." SCIENCE VOL 302
Abstract: Nonobese diabetic (NOD) mice are a model for type 1 diabetes in humans. Treatment of NOD mice with end-stage disease by injection of donor splenocytes and complete Freund's adjuvant eliminates autoimmunity and permanently restores normoglycemia. The return of endogenous insulin secretion is accompanied by the reappearance of pancreatic ß cells. We now show that live donor male or labeled splenocytes administered to diabetic NOD females contain cells that rapidly differentiate into islet and ductal epithelial cells within the pancreas. Treatment with irradiated splenocytes is also followed by islet regeneration, but at a slower rate. The islets generated in both instances are persistent, functional, and apparent in all NOD hosts with permanent disease reversal.

Shinichiro Ryu, Shohta Kodama, Kazuko Ryu, David A. Schoenfeld, and Denise L. Faustman. 2001. "Reversal of established autoimmune diabetes by restoration of endogenous β cell function." The Journal of Clinical Investigation, Volume 108, Number 1 (http://www.jci.org/articles/view/12335/pdf)

Airaghi, L; Tedeschi, A. 2006. "Negative association between occurrence of type 1 diabetes and tuberculosis incidence at population level." Acta Diabetologica 43(2):43-45.
Abstract: In the last decades of the 20th century, the incidence rate of type 1 diabetes increased in affluent countries. The pattern of occurrence of this autoimmune disease over time could provide helpful information to discriminate between alternative aetiologic hypotheses. In addition to genetic disposition, the incidence of type 1 diabetes seems to be conditioned by environmental factors and lifestyle. One theory proposes that the increase in the prevalence of autoimmune diseases is a result of the decrease in the incidence of childhood infections. To investigate the relationship between the incidence of type 1 diabetes and the decline of infectious diseases, we calculated the correlation between the occurrence of type 1 diabetes and tuberculosis in several European and non-European countries. The results of our analysis demonstrate an inverse correlation between the occurrences of type 1 diabetes and tuberculosis. A possible interpretation of this negative association is that a high socio-economic status and a westernised way of life imply a reduced or delayed exposure to infectious agents and so a reduced or delayed “pressure” on the immune system, which is free to mount inappropriate responses against self-antigens, as happens in type 1 diabetes.

Emanuela Martinuzzi, Giulia Novelli, Matthieu Scotto, Philippe Blancou, Jean-Marie Bach, Lucy Chaillous, Graziella Bruno, Lucienne Chatenoud, Peter van Endert, and Roberto Mallone. 2008. "The Frequency and Immunodominance of Islet-Specific CD8+ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment." Diabetes 57:1312-1320. (http://diabetes.diabetesjournals.org/cgi/content/full/diabetes;57/5/1312)

Bart O. Roep. 2008. "Islet Autoreactive CD8 T-cells in Type 1 Diabetes." Diabetes 57:1156 (http://diabetes.diabetesjournals.org/cgi/content/extract/57/5/1156)

Jean-François Bach. 2002. "The Effect of Infections on Susceptibility to Autoimmune and Allergic Diseases." The New England Journal of Medicine, Volume 347:911-920. (http://content.nejm.org/cgi/content/full/347/12/911?ijkey=93527d6a9ffb63beb014b0f505015da7d65b4198&keytype2=tf_ipsecsha)

Hui-Yu Qin and Bhagirath Singh. "BCG Vaccination Prevents Insulin-Dependent Diabetes Mellitus (IDDM) in NOD Mice after Disease Acceleration with Cyclophosphamide." Journal of Autoimmunity, Volume 10, Issue 3, June 1997, Pages 271-278.
Abstract: We have previously shown that immunotherapy with complete Freund's adjuvant (CFA) or BCG is highly effective in the prevention of spontaneous insulin-dependent diabetes mellitus (IDDM) and in circumventing the rejection of syngeneic islet grafts in diabetic NOD mice. This protection is reversed by treatment with cyclophosphamide (Cy). The present study was undertaken to determine the effect of BCG vaccination on the progression of Cy-accelerated diabetes in NOD mice and to understand the mechanism of BCG immunotherapy. The time course of Cy and BCG administration showed that the progression of Cy-induced diabetes can only be blocked when BCG vaccination is given within 3 days of Cy administration. Mice given BCG 3 days before (−3 days) or 7 days after Cy treatment were not protected. BCG immunization 1 day after Cy treatment almost completely prevented insulitis in the islets of Cy-treated mice. Cy treatment reduced the endogenous production of anti-GAD67 antibody, whereas BCG vaccination 1 day after Cy treatment restored the production of anti-GAD67 antibody of IgG1 isotype. The comprehensive effect of BCG vaccination on cytokine production in Cy-treated mice was to increase IL-4 production and change the IL-4/IFN-γ ratio in both serum and supernatant of spleen cell cultures. We found that BCG-induced protection was associated with increased splenic CD4+CD45 RBhighT cells. Taken together, our results indicate that BCG treatment counteracts the effect of Cy on autoimmune process in IDDM. However, BCG immunotherapy has a narrow window of up to 3 days after Cy treatment to block the progression of Cy-induced diabetes and to allow for the induction of regulatory cells which may effectively downregulate the diabetogenic cells. In summary, our results suggest that BCG vaccination prevents IDDM if given in the prediabetic state. After the induction of diabetes, disease progression can only be prevented within a narrow window of opportunity by this treatment.

[danismom79]

Liqin Ban, Jack Zhang, Limei Wang, Willem Kuhtreiber, Douglas Burger, and Denise L. Faustman. 2008. "Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism." PNAS published ahead of print August 28, 2008, doi:10.1073/pnas.0803429105 (http://www.faustmanlab.org/Publications/PNAS2008.pdf)
Abstract
Human autoimmune (AI) diseases are difficult to treat, because immunosuppressive drugs are nonspecific, produce high levels of adverse effects, and are not based on mechanistic understanding of disease. Destroying the rare autoreactive T lymphocytes causing AI diseases would improve treatment. In animal models, TNF selectively kills autoreactive T cells, thereby hampering disease onset or progression. Here, we seek to determine, in fresh human blood, whether TNF or agonists of TNF selectively kill autoreactive T cells, while sparing normal T cells. We isolated highly pure CD4 or CD8 T cells from patients with type 1 diabetes (n = 675), other AI diseases, and healthy controls (n = 512). Using two cell death assays, we found that a subpopulation of CD8, but not CD4, T cells in patients' blood was vulnerable to TNF or TNF agonist-induced death. One agonist for the TNFR2 receptor exhibited a dose-response pattern of killing. In type 1 diabetes, the subpopulation of T cells susceptible to TNF or TNFR2 agonist-induced death was traced specifically to autoreactive T cells to insulin, a known autoantigen. Other activated and memory T cell populations were resistant to TNF-triggered death. This study shows that autoreactive T cells, although rare, can be selectively destroyed in isolated human blood. TNF and a TNFR2 agonist may offer highly targeted therapies, with the latter likely to be less systemically toxic.

Supporting Information (http://www.pnas.org/content/suppl/2008/08/28/0803429105.DCSupplemental/0803429105SI.pdf)

[My_Dana]

Link to article (http://www.medpagetoday.com/Endocrinology/Diabetes/tb/10656)

BOSTON, Aug. 25 -- Laboratory studies of type 1 diabetes and other
autoimmune diseases show that boosting levels of tumor necrosis factor
(TNF) or its receptor activity selectively destroys autoreactive T cells,
suggesting a possible cure for the diseases, investigators here reported.

Administration of TNF or a receptor agonist to isolated T-cells led to the
death of a subpopulation of autoreactive CD8 cells to insulin, Denise
Faustman, M.D., Ph.D., of Massachusetts General Hospital, and colleagues
reported online in Proceedings of the National Academy of Sciences.

CD4 cells and other populations of autoreactive CD8 cells proved invulnerable
to TNF- or agonist-induced death.

Action Points

* Explain to patients that the study suggests that neutralizing specific
cells implicated in type 1 diabetes and other autoimmune diseases may offer
a new approach to treatment.

* Note that the findings were based on laboratory studies of blood
samples, not a randomized, clinical trial.

Using an animal model of type 1 diabetes, the investigators had previously
shown that TNF-triggered cell death led to regeneration of normal pancreatic
islet cells to replace those destroyed by autoreactive T-cells.

"With chronic diseases such as diabetes and other forms of autoimmunity,
most therapies have traditionally used nonspecific immunosuppression,
because it was thought that the rare autoreactive T cells could not be
identified, much less selectively killed," the authors said.

"A defective NF signaling pathway, which leads to cell death, now provides,
at least in vitro, a unique opportunity in human [autoimmune] diseases to kill
only autoreactive T cells"

Noting that anti-TNF therapy has become a mainstay of treatment for
rheumatoid arthritis and Crohn's disease, both autoimmune disorders, the
authors said, "an expanding body of research in animal models . . . suggests
the opposite strategy may be warranted."

Genetic and functional studies have implicated deficiencies in TNF levels or
signaling pathways in human autoimmunity, suggesting that therapy to raise
levels of the immunoregulatory cytokine or restore normal signaling may have
a role in human autoimmune diseases.

Continuing their investigation of TNF's role in autoimmunity, Dr. Faustman
and colleagues studied blood specimens from 675 patients with type 1
diabetes, from patients with other autoimmune diseases, and from 512
healthy individuals.

The investigators isolated CD4 and CD8 T cells from the blood samples. In a
series of experiments, TNF or an agonist to TNF receptor 2 was added to the
samples.

Two different cell-death assays demonstrated that a subpopulation of CD8
cells succumbed to the cytokine and the receptor agonist. CD4 cells and
other CD8 subpopulations were unaffected.

The researchers subsequently traced the activated T cells involved in type 1
diabetes to an autoreactive CD8 subpopulation that specifically targets
insulin, which is a known autoantigen.

"This study shows that autoreactive T cells, although rare, can be
selectively destroyed in isolated human blood," the authors concluded. "TNF
and TNF [receptor 2] agonist may offer highly targeted therapies, with the
latter likely to be less systemically toxic."

The results also support an ongoing phase I clinical trial involving patients
with type 1 diabetes treated with bacillus Calmette-Guerin, which transiently
elevates TNF levels.

[My_Dana]

From the above article -

"..TNF or an agonist to TNF receptor 2.."

What is the agonist she used here?
Is this referring to the BCG vaccine?

[danismom79]

From the above article -

"..TNF or an agonist to TNF receptor 2.."

What is the agonist she used here?
Is this referring to the BCG vaccine?

I'm not exactly sure. I sent the lab an email.

From my second post above, in the Supporting Information section, she used a variety of what were called agonist antibodies. This is one of them. http://www.cellsciences.com/PDF/HM2008.pdf

[danismom79]

Does anyone have information about copyright violations? I deleted a couple of articles that I had in PDF form. Dr. Faustman HERSELF emailed me the latest article that My_Dana posted about and I'd like to share it, but I don't want to break any regulations.

I think I can email it if you PM me, but putting it on a forum is different.

[My_Dana]

Does anyone have information about copyright violations? I deleted a couple of articles that I had in PDF form. Dr. Faustman HERSELF emailed me the latest article that My_Dana posted about and I'd like to share it, but I don't want to break any regulations.

I think I can email it if you PM me, but putting it on a forum is different.

I would say if she sent articles to you and/or it's on the web, then most likely it has been published and is already public knowledge.

What I posted previously was a posted article.

I would like a copy of what you have. Buggle and I have a paper from Prof/Researcher Dana Spence (male)
from the Univ of MI. Some great stuff on c-peptide research. He and I spoke
about posting the content. Not yet.

[danismom79]

Carmen (on the Parents of Children with Type 1 forum) posted this video (http://vimeo.com/1435650) of an interview with Dr. Faustman by Diabetes Daily.

PDF Transcript (http://www.diabetesdaily.com/edelman/2008/09/01/diabetes-cure-trial.pdf)

[brokenheart]

Carmen (on the Parents of Children with Type 1 forum) posted this video (http://vimeo.com/1435650) of an interview with Dr. Faustman by Diabetes Daily.

PDF Transcript (http://www.diabetesdaily.com/edelman/2008/09/01/diabetes-cure-trial.pdf)

I have been following Dr. Faustman's research, too. I have read the interview transcript twice. I don't understand all of it, but was excited about it.

That said, I think most of us know that JDRF is not funding her research. I googled a little and found that Dr. Diane Mathis of Hardvard (http://www.hms.harvard.edu/dms/immunology/fac/Mathis.html) did not think that Dr. Faustman's approach is feasible with humans. In her letter to the New York Times in 2004, which was not published, she says:

But it is perhaps most important to correct the misconception that the curative procedure Dr Faustman has used in mice is ready for translation to humans. This procedure entails injecting two major ingredients into recently diabetic mice. The first is a drug similar to one called BCG that is a common component of vaccines, such as the vaccine against TB. The second is an enormous quantity of spleen cells - the equivalent in humans would be the injection of cells from 5 human spleens over a period of 4 years. This procedure simply can't be done in humans.

(cf: http://www.diabeteshealth.com/read/2005/05/01/4126.html )

Some of you may have read it. What do you think?

In the same unpublished letter, Dr. Mathis also says that

Multiple scientific groups have cured diabetes in mice by multiple means. In fact, two of the most promising clinical trials currently being conducted on type-1 diabetes patients are based on a report published in the Proceedings of the National Academy of Sciences in 1994 that injection of a particular antibody into mice cures them of their diabetes.

So, Dr. Faustman does not seem to be the only researcher who has cured diabetic mice.

Interestingly, the same page at diabeteshealth.com says that Dr. Mathis is replicating Dr. Faustman's research:

Diane Mathis herself is heading up a new $5 million JDRF project: Islet Regeneration During Reversal of Autoimmune Diabetes in NOD Mice. Curiously, the name of this study is nearly identical to the title of the paper Faustman published in the November 14, 2003 issue of Science: “Islet Regeneration During the Reversal of Autoimmune Diabetes in NOD Mice.”

[brokenheart]

By the way, one thing that baffles me is that I read all the time that researches are being done to find a means to regenerate insulin-producing islet cells.

Well, again, I am a lay man, but I read somewhere else that T1D patients' pancreas still constantly produce islet cells, but which are soon destroyed by their immune system.

If that's the case, what's the point of RE-generating islet cells without correcting the immune system?

Another point I wanna make is that, any "cure" involving transplantation/immunosuppressant drugs does not sound exciting to me at all. What do you guys think?

[danismom79]

I wish I knew how to keep all the quotes within a quote...

I have read that letter by Mathis and Benoist. That one, and a response, are included here: http://www.islet.org/forum/messages/36196.htm

Some choice quotes from the response:

They then claim that multiple scientific groups have cured diabetes in mice by multiple means and give the one example of promising clinical trials
currently being conducted based on a study published in the Proceedings of the National Academy of Sciences in 1994. They fail to disclose that this study showed only new-onset diabetic mice, with remaining functioning islets, experienced a halt in disease progression.

I'm not 100% sure, but I suspect this (http://www.pnas.org/content/91/1/123.full.pdf) is the 1994 paper they were referencing.

Dr. Faustman's 2001 40-day treatment protocol stands alone for a number of reasons. First, it not only interrupted the progression to full-blown
diabetes in the earlier stages but was also successful at end-stage disease in the mice for the first time ever. There was total elimination of the disease. There was a return of normal insulin secretion resulting in normal blood glucose levels for the lifetime of the mice without further treatment. No other data has been published that can produce such results to be called a "cure".

Dr. Mathis and Dr. Benoist propose that Dr. Faustman must inject an enormous quantity of spleen cells into humans as a second step and this procedure simply cannot be done. Have they actually read Dr. Faustmans' papers? Did they actually read the New York Times article? They could not be more mistaken because Dr. Faustman and Dr. Nathan are not proposing to inject spleen cells into humans as any part of a treatment.

And a response from Faustman: http://www.islet.org/forum/messages/36531.htm

Keep in mind that this was all about 4 years ago. JDRF funded 3 different teams to replicate her work, and they got the same results - except for the bit about spleen cells migrating to the pancreas. But regardless of where the cells came from, the mice did indeed start producing their own insulin again.

[danismom79]

By the way, one thing that baffles me is that I read all the time that researches are being done to find a means to regenerate insulin-producing islet cells.

Well, again, I am a lay man, but I read somewhere else that T1D patients' pancreas still constantly produce islet cells, but which are soon destroyed by their immune system.

That is my understanding too.

If that's the case, what's the point of RE-generating islet cells without correcting the immune system?

EXACTLY!

Another point I wanna make is that, any "cure" involving transplantation/immunosuppressant drugs does not sound exciting to me at all. What do you guys think?

Not appealing at all. Besides the awful side effects that can be worse than the disease, Faustman's research has shown that the immune system needs to be stimulated to fight autoimmunity.

[brokenheart]

Cool danismom, you learnt how to quote the quote, didn't ya? And thanks a lot for the info on Dr. Faustman's response to Dr. Diane Mathis. I appreciate work of both of them.

From what I read in the interview PDF, Dr. Faustman's phase 1 human trial will have a result by the end of 2009, right? I am wondering if we could do something to raise a little funds for her research.

[brokenheart]

That is my understanding too.


EXACTLY!


Not appealing at all. Besides the awful side effects that can be worse than the disease, Faustman's research has shown that the immune system needs to be stimulated to fight autoimmunity.

You know, I don't quite understand why JDRF seems to be going in that rout? Or is it just my misunderstanding?

To me, transplantation/taking immunosuppressant drugs is worse than managing diabetes with a pump and CGM.

[WestinsMom]

I got this today on another list. I don't know if it is what was being discussed in this topic or not.

http://www.diabetesdaily.com/edelman/2008/09/01/diabetes-cure-trial.pdf

[danismom79]

I got this today on another list. I don't know if it is what was being discussed in this topic or not.

http://www.diabetesdaily.com/edelman/2008/09/01/diabetes-cure-trial.pdf

Yes, that's the transcript from a video interview with Diabetes Daily. Have you seen the video? It's back on page 1.

[WestinsMom]

Does the video take a long time to load? It doesn't seem to be working for me.

[Jaclyn's Mom]

Taking immunosupressant drugs can have side effects that are worse than having type 1, so I don't want that for my daughter. Eventually, those transplanted cells are going to undergo the same process, because the autoimmune process is still present in the body.

Dr Faustman's research halts the autoimmune attack, killing off only the "bad" cells that attack the islets. It's a 2 -step process. First, it stops the "bad" white cells from being produced in the marrow.(immunity restored) Then the second step is the killing of the cells that attack the islets.

[lovelady]

Please write to JDRF and encourage them to support Faustman's research. We have been raising money for the Walk on October 26th and I sure would like that money to go to her progress! Please pray as well. The creator of the universe knows NO limits! Let us all lift our children up to Him each day and ask for healing.

[danismom79]

Please write to JDRF and encourage them to support Faustman's research. We have been raising money for the Walk on October 26th and I sure would like that money to go to her progress! Please pray as well. The creator of the universe knows NO limits! Let us all lift our children up to Him each day and ask for healing.

Unfortunately they have denied her request to even ask them for funding.

[danismom79]

There is a blog post (http://cureresearch4type1diabetes.blogspot.com/2008/10/faustmans-research-part-1-history.html) on the history of Dr. Faustman's research. If anyone spots discrepancies, please contact the author, or leave a comment on his blog.

ETA: This person has made some false statements in his blog post, so please - if you see them, point them out. For those of you just learning about Dr. Faustman and her work, that blog is not the place to start.

[Jaclyn's Mom]

The best place to get info about Dr Faustman's research is www.faustmanlab.org . There is an e-mail address that you can contact for any questions. Do not count on anyone's blog to give true and accurate information.

[jet59or]

http://www.faustmanlab.org/news.html

They are starting to screen for Phase II trials. I would have liked to see some results, or even just some observations, from Phase I, but since it's not over until 2010, I suppose that is standard procedure. Still, planning on Phase II and even III gives some hope that they see some benefits.

[brokenheart]

http://www.faustmanlab.org/news.html

They are starting to screen for Phase II trials. I would have liked to see some results, or even just some observations, from Phase I, but since it's not over until 2010, I suppose that is standard procedure. Still, planning on Phase II and even III gives some hope that they see some benefits.

That does sound exciting. So, are you saying that they have started on Phase II even before Phase I is complete? I'll keep my fingers crossed for their results.