Thursday, June 11, 2009

Characteristics of the Innate Immune ResponseMelanoma ..Jim Breitfeller

The immune system protects against pathogens that penetrate the physical barriers of the skin and mucous membranes lining the digestive, respiratory, and reproductive tracts. It is subdivided into the innate and the adaptive immune systems. These two systems work differently, but collaboratively, to provide a powerful defense against microbial invaders. Increasing evidence suggests that the immune system also plays a role in detecting and eliminating tumor cells, and can be manipulated therapeutically against cancer.

Innate Immunity

Characteristics of the Innate Immune Response

The innate immune system provides a rapid but nonspecific response to the most common foreign pathogens.1 This system, in some form, is present in all animals, and some elements of it have existed for more than 500 to 700 million years.2 Cells of the innate immune system have specialized receptors (eg, Toll-like receptors) that recognize molecular structures or patterns that are characteristic of—and often indispensable parts of—common pathogens.3 As such, they recognize these pathogens immediately, even without having encountered them previously, and can react promptly. Disadvantages of the innate immune system are that it can recognize only a limited number of molecules, has limited ability to recognize viruses once they have entered normal cells, and has no "memory" and therefore cannot provide lasting protective immunity against these molecules.
The innate immune system is often sufficient to protect against the small quantities of common pathogens humans come into contact with on a day-to-day basis.2 When additional "help" is needed, the innate immune system activates and modulates the adaptive immune system.2,3
Cells of the Innate Immune Response

Macrophages are the "sentinels" of the immune system. Present in large quantities under the skin, in the lungs, and in the tissues surrounding the intestines, these cells are in key positions to detect microbes where they first enter the body.2 The name macrophage means "large eater," and its primary responsibility is to rid the body of debris as well as pathogens, largely but not exclusively via phagocytosis.2,3

In their usual resting state, macrophages sample their environment and serve as "housekeepers," scavenging dead cells, cellular debris, oxidized lipoproteins, and other normal cellular by-products.2,3 When exposed to certain cytokines (eg, interferon gamma) released by other immune cells, such as helper T-cells and natural killer cells, macrophages become primed or activated. The activated macrophage engulfs a pathogen, containing it in a phagosome, which then fuses with a lysosome full of antimicrobial enzymes that destroy the pathogen. After digesting the pathogen, macrophages release various chemicals that increase the flow of blood to the area, trigger capillaries to allow extravasation of blood cells into the affected tissue, stimulate pain signals from nerves in the area, and release cytokines that facilitate communication with other cells in the immune system. As will be described in more detail later, activation also causes the macrophage to upregulate major histocompatibility complex (MHC) class II receptors on its cell surface, and protein fragments from the invading pathogen are transported to the MHC receptors and presented there for detection by helper T-cells and natural killer cells.2

Macrophages also have cell surface receptors (eg, the Toll-like receptors mentioned above) that enable them to detect molecules (eg, lipopolysaccharide, mannose) that are not normally found on human cells but are common cell wall components in typical pathogens.2 When a macrophage detects such molecules, it becomes "hyperactivated." The macrophage stops proliferating and becomes a virtual killing machine, growing larger and increasing the number of lysosomes and its rate of phagocytosis. It also actively migrates toward a foreign invader, even extending out "feet" to grab it up.2 In this state, macrophages also secrete tumor necrosis factor (TNF) alpha, interleukin (IL) 1, IL-6, and IL-8. These inflammatory cytokines help kill tumor cells and virus-infected cells and activate and summon other cells in the immune system.2,3

Neutrophils are highly phagocytic cells. Produced from myeloid precursors and with a lifespan of only 2 to 5 days, these cells circulate through the bloodstream, where they are within easy reach of all cells in the body until they are summoned.2,3

Cytokines and chemokines released by macrophages and mast cells draw neutrophils to the area of infection.2,3 It takes only about 30 minutes for neutrophils to exit the bloodstream and arrive fully activated at the site of an infection.2 Once there, they not only perform phagocytosis, they secrete cytokines (eg, TNF) to summon other immune cells and release various antimicrobial products from granules into the extracellular space.1-3

Mast cells and eosinophils.

These cells lie beneath exposed surfaces of the body (ie, the skin and mucosal barriers) and can survive for years. Their best-known function is to provide a defense against parasites. Mast cells are phagocytic and also contain granules of chemicals, most notably histamine. Eosinophils are poor phagocytes but do carry granules. When a mast cell or eosinophil detects a parasite, it "degranulates," that is, it unloads the chemicals.

Contributing Writer: Lauren Cerruto
Contributing Editor: Bernard A. Fox, PhD
Editor-in-Chief: Jeffrey S. Weber, MD, PhD


Take Care,

Jimmy B

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Greetings to One and All

This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.

It was he, who showed me How to live and give back. He was wise beyond his years.

Kenny B

Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller

My Profile as of 2009

My photo
Last July (2005)I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home. I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08


The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking.

It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.


So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19

IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.

By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.

The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. As stated previously, CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history,

On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23

Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome.

All it takes is that one magic bullet to start the immune reaction..

Melanoma And The Magic Bullet (Monoclonal Antibodies)

Public Service Announcement

A call for Melanoma Patients by Dr. Steven A Rosenberg

"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.

"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."

If you would like to apply for his trials, here is the website and information.

Dr. Rosenberg's information

Dr. Rosenberg's Clinical Trials

For the Warriors

The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.

Source Fastcures blog

Join the Relay for Life!!!


Dear Family and Friends,

I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.

To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary

Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:

CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.

REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.

FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.

Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.

Keep the Fire Burning!!!



Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by " : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma

Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma

Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver.

This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”

Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.

Current Trial Centers

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)

Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.

Is there some way to post this “Call for Patients” on the web site?

Steve Rosenberg

Dr. Rosenberg's Clinical Trials

(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.