The hormone that holds key to HIV cure may also Help in Melanoma Therapy..Jim Breitfeller

The hormone that holds key to HIV cure may also Help in Melanoma Therapy.

The hormone that holds key to HIV cure may also shift the balance of the immume system to activation. By increasing the Hormone IL-7 during therapy, you could shut down the SOCS3 expression giving rise to the TH1 Phenotype needed for the immune response.

Source:The hormone that holds key to HIV cure




“The researchers increased levels of the hormone IL-7, the gene SOCS-3 “switched off” and the trial mice were able to gradually eliminate the HIV from their bodies, says the main study published in the February 4 2011 issue of the journal Cell.”

SOCS3 inhibits TH1 Phenotype
SOCS3 inhibits TH17 Phenotype
SOCS3 activates TH2 phenotype





Is it possible by the raising the IL-7 concentration, pushes the T-cell differentiation towards the TH1/TH17 phenotypes. If that is the case, the oncologists have another knob to turn to involke an immune response.







“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~


Take Care,

Jimmy B

Tumors shut down the Third Signal needed for T-cell Activation..Melanoma Cancer..Jim Breitfeller

A picture is worth a thousand words.

STAT-3 signaling from the tumors blocks the pro-inflammatory cytokines, so no danger signal is sent to the immune system.




The Missing Link in T-cell activation using a Vaccine, "The Danger Signal"

DCs leads to enhanced induction of Th17-1 cells. These data demonstrate the capacity of DCs to induce expansion of polyfunctional IL17-producing T cells in humans, and suggest a role for DCs in the enrichment of Th17-1 cells in the tumor bed.

Tumor bed is heavily infiltrated by DCs, which, as shown here, are the most efficient inducers of human Th17 cells. The data supports a model in which Th17 cells are recruited to the tumor bed by Th17-attracting chemokines (eg, CCL20, recently shown to be enriched in the melanoma tumor bed) and activated to a Th17 phenotype locally by tumor-infiltrating DCs. The capacity of DCs to induce Th17 cells may be further enhanced by the uptake of apoptotic tumor cells, as well as inflammatory cytokines (eg, IL1, IL6, TNF) in the tumor bed. This gives rise to T-cell activation and the inflamed response leading to immune response.


For the tumor to survive the immunologic suppression system, it must turn on pathways (such as Stat3) that inhibit production or sensing of proinflammatory danger signals that activate innate and adaptive immune responses. Tumors that successfully accomplish this can shift the balance of immunity from activation to tolerance induction. Pardol et al But what if, the production of Proinflammatory cytokines can over come the suppressive function of the tumor’s microenvironment? Could the differentiation of the CD4+ T-cells into Th17 be the path to activation and immunity responses? If that is the case, then Anti-CTLA-4 blockade (ipilimumab) plays more of a major factor in adaptive immunity then we originally thought.




“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

NIH Scientists Discover Secrets Of Helper T Cells Involved In Autoimmunity..Melanoma..Jim Breitfeller

NIH Scientists Discover Secrets Of Helper T Cells Involved In Autoimmunity
October 21, 2010

A race for a cure!!!!!!! Let the games begin!!!!!


WHATScientists at the National Institutes of Health have redefined the roles of several cytokines involved in the generation of immune cells implicated in severe autoimmune diseases. The study in mice showed that development of Th17 immune cells can occur without the presence of transforming growth factor (TGF)-beta, a mediator thought to be required for Th17 cell development. The study demonstrates that the interaction of three inflammatory cytokines (proteins that influence the behavior of cells) - interleukin-6 (IL-6), IL-1-beta and IL-23 - is responsible for the creation of Th17 cells that are more active in promoting autoimmunity than Th17 cells generated with IL-6, IL-1-beta and TGF-beta. These findings reemphasize the separate roles of IL-23 and TGF-beta in immunity and autoimmunity, and open up possibilities for the development of new therapies. The study appears in the current issue of the journal Nature.

The immune systems of mice and humans mainly consist of B cells and T cells. While B cells fight infections and can induce autoimmunity by producing antibodies that directly target foreign antigens or a person's own tissue, T cells are involved in overall cell-mediated immunity. Importantly, how a T helper (Th) cell differentiates (develops from an immature, unspecialized cell into a mature, specialized cell) determines how it mediates immune responses. Th17 cells produce IL-17, a powerful inflammatory cytokine, and have been implicated in multiple autoimmune diseases, including rheumatoid arthritis, psoriasis and multiple sclerosis. The established belief has been that Th17 cells initially differentiate in response to activation by IL-6 and TGF-beta. However, previous research has shown that TGF-beta is primarily associated with suppressing immune functions and promoting regulatory T cells (Treg), which can produce inhibitory cytokines that dampen inflammatory immune responses.

In the present study, the NIH scientists first looked at the conditions to differentiate Th17 cells from naïve T cells outside of the mouse (in vitro) and tried several different cocktails of cytokines to see which combinations would promote Th17 development. They found two combinations that efficiently induced Th17 differentiation. As previously described, IL-6, IL-1-beta, and TGF-beta-1 together created Th17 cells. Surprisingly, IL-6, IL-1-beta, and IL-23 without TGF-beta also created Th17 cells. Most interestingly, the action of Th17 cells generated with IL-23, designated Th17(23), was different from the action of Th17 cells generated with TGF-beta (Th17(beta)). The researchers compared transcription factors, receptors and mediators of the two Th17 subtypes and looked at the pathogenic activity of both Th17 subtypes in mice during experimental autoimmune encephalomyelitis (EAE), a common model of autoimmunity that mimics some aspects of multiple sclerosis. They found that Th17(23) cells provoked significantly more severe disease than did Th17(beta) cells.

These findings suggest a new model for Th17 generation and the existence of functionally different subtypes of Th17 cells. This study also provides a better understanding of the array of immune components involved in autoimmunity and suggests possibilities for new targeted therapies.

NIH scientists contributing to this study are affiliated with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Dental and Craniofacial Research (NIDCR), and the National Institute of Allergy and Infectious Diseases (NIAID). Additional support was provided by Merck Research Laboratories (Schering-Plough Biopharma), Palo Alto, Calif.

REFERENCE
Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel J, Ramos HL, Wei L, Davidson T, Bouladoux N, Grainger J, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach E, Belkaid Y, Cua DJ, Chen W, O'Shea JJ. Enhanced Pathogenicity of Th17 cells Generated in the Absence of Transforming Growth Factor-ß Signaling. Nature. 2010 October 21;467(7318): 967-971.

WHO
John J. O'Shea, M.D. Scientific Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, is available to comment on this article.

CONTACT
To schedule interviews, please contact Trish Reynolds, 301-496-8190, .

About National Institute of Arthritis and Musculoskeletal and Skin Diseases
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information, visit http://www.niams.nih.gov.

About The National Institute of Dental and Craniofacial Research
The National Institute of Dental and Craniofacial Research (NIDCR) is the Nation's leading funder of research on oral, dental, and craniofacial health. For more information, visit http://www.nidcr.nih.gov/.

About National Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases (NIAID) conducts and supports research -- at NIH, throughout the United States, and worldwide -- to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. For more information, visit http://www.niaid.nih.gov.

About National Institutes of Health
The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information, visit www.nih.gov.

SOURCE: National Institutes of Health

NIH Scientists Discover Secrets Of Helper T Cells Involved In Autoimmunity
October 21, 2010




“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,

Jimmy B

Invoking an Immune Response without causing an Autoimmune Response..Melanoma ..Jim Breitfeller

Challenges in immunotherapy

• Immunotherapy has yet to fulfil its clinical potential.
• Historically, responses have only been observed in a minority of patients.

• Recent trials of new immunotherapies in oncology have shown that patients receiving treatments such as anti-CTLA-4 therapy respond differently, and sometimes later, compared with those receiving chemotherapy or some of the existing immunotherapies such as interleukin-2 and interferon.

Some of the investigational immunotherapies act as T-cell mediated immunopotentiators. That is, they may regulate and potentially enhance the body’s own immune response, and consequently there may be a delay in stimulating the immune system to fight disease.



"Another patient’s measured tumor burden in 7 pulmonary metastases is shown as a percent of their baseline size. Tumor remained stable during 4 doses of ipilimumab administered without symptoms, but regressed promptly after patient experienced a bout of biopsy documented enteritis." Yang et al

Source:http://pathology2.jhu.edu/hypophysitis/pdf/531_2007_Yang.pdf

en•ter•i•tis ( n t -r t s). n. Inflammation of the intestinal tract.

Inflammation is the "Danger Signal" that is needed to hone in on the cancer itself.


Currently it is difficult to select patients who might benefit from specific immunotherapeutic approaches, and tailored immunotherapy regimens will have to be created in order to provide the most appropriate and effective treatment. Each Patient is at a different stage of his or her disease. It will take a trained Melanoma Oncologist to provide the guidance.

T-cell activation video from Andrew Lamb on Vimeo.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Helper T Cell (Th17) Guides Killer Cells to Melanoma Cancer..Jim Breitfeller

Cancer manages to suppress or elude the body's immune system to survive and grow. Scientists at The University of Texas M. D. Anderson Cancer Center show this week in the journal Immunity how the helper T cell Th17 awakens the immune system to attack cancer. Senior author Chen Dong discusses the findings and their potential application for patients.

Helper T Cell Guides Killer Cells to Cancer


An important mechanism by which Melanoma cancer avoids antitumor immunity is by recruiting regulatory T cells (Tregs) to the tumor microenvironment. Recent studies suggest that suppressor Tregs and effector Th17 cells share a common lineage and differentiate based on the presence of certain cytokines in the microenvironment. Because IL-6 in the presence of TGF-β has been shown to inhibit Treg development and induce Th17 cells, they hypothesized that altering the tumor cytokine environment could induce Th17 and reverse tumor-associated immune suppression.



CTLA-4–B7 Interaction on the activated T-cell suppresses Th17 Cell Differentiation.Using anti-CTLA4 blocking antibody (Ipilimumab or tremelimumab) increases Th17 cells in peripheral blood of patients with metastatic melanoma. The Th17 cells can then migrate to the tumor's microenviroment. This sends the Danger Signal in the form of pro-inflammatory cytokines including IL-17. This is the third signal that is needed in the initiating of an immune response.

One of the mechanisms proposed is that CTLA-4 inhibition of T cell activation is due to antagonism of CD28-mediated costimulation. Both CD28 and CTLA-4 share the ligands B7.1 (CD80) and B7.2 (CD86); however, the affinity of the CTLA-4:B7 interaction is 10 times higher than the affinity of the CD28:B7 interaction. Although studies using CD28-deficient mice have shown that negative signaling through CTLA-4 is independent of CD28 expression, it is plausible that CTLA-4 interacts with B7 and prevents its interaction with CD28.

It is possible that T-cell activation can’t start until the level of CTLA-4 is block or decreased.

In my own experience, I did not get any activation until tremelimumab was introduced

If you Block the CTLA-4 and B7 with Ipilimumab or tremelimumab It will also take the brakes off the immune system and shift it towards activation.




I hypothesized that Th17 cells induce Th1-type chemokines, and in turn recruit Th1-type effector T cells into tumor microenvironment.

Recent data supports the notion that Th17 cells induce Th1-type chemokines through IL-17 and IFN- , and in turn recruit Th1-type effector T cells and NK cells into tumor microenvironment.

Increased tumor-associated IL-17 predicts improved patient survival

Mechanistically, Th17 cell–derived IL-17 and IFN- synergistically induced the production of CXCL9 and CXCL10, and in turn promoted effector T-cell migration toward tumor. The levels of CXCL9 and CXCL10 were directly correlated with tumor-infiltrating CD8+ T cells and NK cells. The data suggest that Th17 cells may play a role in promoting effector T-cell and NK-cell tumor trafficking and retainment, and the polyfuctional cytokine profile (IFN- +IL-17+) of Th17 cells is essential for synergistically inducing Th1-type chemokines.

Source:http://bloodjournal.hematologylibrary.org/cgi/content/full/114/6/1141



“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~
Take Care,
Jimmy B

The missing third signal "The Danger Signal"Melanoma..Jim Breitfeller

Th17 Cells Secrete IL-17 in the Tumor Microenvironment causing inflammatory symptoms "The Danger Signal"improves Survival in a Murine Model of Pancreatic Cancer and in Melanoma also.

Third, inflammatory cytokines, including IL-1, IL-6, IL-12, and IFN-γ provide a third signal that acts directly on T cells, referred to as the “danger signal”. This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells.

"Th17 cells and IL-17 participate in antitumor immunity by facilitating T cell recruitment to the tumor site and CD8+ T cell priming and effector differentiation suggests a new avenue for developing Th17 cell-based therapy."

~S. A. Rosenberg~


"Using in vitro and in vivo approaches, we determined that under neutral conditions, simultaneous activation of Tregs and naive CD4+ conventional T cells in the presence of APCs resulted in conversion of Tregs into IL-17–producing cells, and endogenous IL-1β was mandatory in this process" according to Vassiliki A. Boussiotis et al



Thus, the addition of IL-6 and IL-1β to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer and Melanoma.

So we need to suppress the Tregs and generate Th17 T-cells to initiate the right immune response.




“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

Th17 Cells Summon an Immune System Strike Against Cancer Melanoma,, Jim Breitfeller

Th17 Cells Summon an Immune System Strike Against Cancer

Released: 10/28/2009 3:35 PM EDT
Embargo expired: 10/29/2009 12:00 PM EDT
Source: University of Texas M. D. Anderson Cancer Center

Newswise — A specific type of T helper cell awakens the immune system to the stealthy threat of cancer and triggers an attack of killer T cells custom-made to destroy the tumors, scientists from The University of Texas M. D. Anderson Cancer Center report in the early online edition of the journal Immunity.

The role of Th17, one of only four known types of T helper cell, opens a possible avenue for overcoming cancer's ability to suppress or hide from the body's immune system, said senior author Chen Dong, Ph.D., professor in M. D. Anderson's Department of Immunology. Dong and colleagues found that Th17 stifled development of metastatic melanoma tumors in the lungs of mice.

"While there is much work to be done, these preclinical findings imply the possibility of taking a patient's Th17 cells, expanding them in the lab, and then re-infusing them as treatment," Dong said. Development of a vaccine to stimulate Th17 cells would be another possible application.

Dong earlier discovered the existence of Th17 cells and established that they secrete the inflammatory protein interleukin-17 (IL-17). His lab showed that overexpression of IL-17 contributes to both autoimmune and inflammatory diseases.

"Th17 cells also are found in a variety of solid tumors and we wanted to know whether these cells promote cancer or play a preventive or protective role," Dong said.

Their research showed that mice made deficient in Th17 cells and then injected with a strain of melanoma that gathers in the lungs experienced aggressive cancer growth compared to mice with normal levels of Th17. At 16 days, tumors in the knockout mice had fused together and coated the lung so extensively that they were no longer countable.

Next, they tested Th17 for preventive effect, injecting Th17 cells primed with tumor-specific antigens and the melanoma cells at the same time. At 16 days, mice with Th17 had low or barely detectable levels of cancer while control mice had a heavy tumor burden in their lungs.

A third set of experiments tested a treatment effect, showing that mice injected with Th17 after they already had melanoma in their lungs had a 75 percent reduction in tumor burden compared with normal mice.

In all experiments, mice with Th17 also had higher levels of several categories of immune system cell than did those with normal or suppressed Th17.

T cells are lymphocytes, a type of white blood cell produced by the thymus equipped with receptors that recognize and bind to antigens, pieces of invading organisms presented to the T cells by dendritic cells. The bound antigen converts the T cell to T helper cells that secrete signaling molecules called cytokines to launch an appropriate immune response. Helper cells, in effect, guide the adaptive immune response.

In the Immunity paper, additional experiments outlined the specific pathway by which Th17 suppresses tumors:

* Tumor invasion of the lung attracts Th17 cells that secrete IL-17A.
* IL-17A in turn promotes the secretion of two chemokines, CCL2 and CCL20, which recruit leukocytes to the tumor site.
* The leukocytes include dendritic cells, which seize tumor antigens and migrate to the lymph nodes.
* There, the antigens are used to prime CD8+ killer cells, which then migrate to the lung and kill established tumors.

The research was funded by grants from the National Institutes of Health, M. D. Anderson's Center for Targeted Therapy, a Leukemia and Lymphoma Society Scholar Award to Dong, and a Trust Fellowship of M. D. Anderson.

Co-authors with Dong and first author Natalia Martin-Orozco, Ph.D., are Yeonseok Chung, Ph.D., Xuexian O. Yang, Ph.D., and Tomohide Yamazaki, all of the Department of Immunology; Pawel Muranski, M.D., and Nicholas Restifo, M.D., both of the National Cancer Institute of the National Institutes of Health; Sijie Lu, Ph.D., of M. D. Anderson's Department of Stem Cell Transplantation and Cell Therapy; and Patrick Hwu, M.D., and William Overwijk, Ph.D., both of M. D. Anderson's Department of Melanoma Medical Oncology.




This expansion of Th17 cells can be done with AntiCTLA-4 blockage

CTLA4 blockade increases Th17 cells in patients with metastatic melanoma..Ribas


Take care

Jimmy B

Melanoma_Missionary


"Today might be the worst day of your life...but tomorrow could be the best. You just have to get there."
~Unknown~