Treatment of Crohns Desease

• Welcome
• Gastro-Intestinal Tract
• Inflammation and Immunity
  • Inflammation
  • Organization
  • Defense Structure
  • Cells involved
  • Cytokines
  • Functional Components
  • Role of TNF- a
• Crohn's Disease and Ulcerative Colitis
• Inflammatory Bowel Disease
  • Causes
  • First line drugs
  • TNF-alpha targeting therapies
  • Herbal Alternative SedaCrohn
  • Surgical Intervention
• Challenges in the Management

Inflammation and Immunity

Inflamation

A Brief Overview

When the body undergoes an infection, inflammation is the immune system's reaction to combat the infection and restore health. The inflammation process also involves amplification and propagation of the processes directed at healing, including the feeling of pain. Pain is a warning sign to the host to do something about what has gone wrong and it prevents further damage since it forces us to make the affected body parts rest.

Classically, the inflammatory process is characterized by redness, warmth, swelling and pain. The chemical substances that mediate inflammation are known as Prostaglandins. Besides inflammation, prostaglandins play a vital role in several other bodily functions. Some of them are as follows:

Prostaglandin	Function
Thromboxane (TXA2)	Promotes formation of thrombus
Prostaglandin I2 (PGI2)	Protects gastric mucosa
Prevents thrombus formation	Prostaglandin E2
Induces inflammation	Induces tumor growth
Prostaglandin D2	Prevents inflammation (anti-inflammatory)
Prostaglandin F2	Loss of parturition

Inflammation is intended to be nature's endowment to facilitate recovery and healing from injury. Unfortunately, unabated, continuous or excessive inflammation can become a disease itself, leading to suffering and sometimes even irreversible damage. In such situations, it becomes imperative to exercise a control over the inflammation. Classically, the inflammation process is stopped by blocking the enzyme which controls the formation of the prostaglandins.

Immunity

A Brief Overview

Essentially, the immune system is our body's defense system. Immunity refers to a series of processes that protect the human body from damage that can result from infections, foreign particles or "errant" cells of our own body. Here we are presenting the information which is important to understand the processes in Inflammatory Bowel Disease and its therapy.

Organization of the Immune System

The immune system is partly inborn and partly acquired. In the process of fighting a cold for example, the immune system gains 'practice' which then makes the body immune to similar germs. The inborn part of the immune system is called innate and the acquired part is called adaptive. Both systems are essential for proper and comprehensive defense against the invading organisms. First, the innate (inborn) system provides the triggers for the activation of the adaptive (acquired) mechanisms. Second, adaptive immune processes deploy some molecules and cells that also participate in the innate process. The two parts of the immune system work together synchronous, efficient and well-orchestrated.

INNATE IMMUNITY This inborn and natural immunity is the first line of defense against all intrusions with the objective of immediate control and containment of infection with general measures. Its onset of action is immediate. It is present in mucosa and skin and defends against all invaders in the same way, that is, its response is non-specific.

ADAPTIVE IMMUNITY Acquired Immunity or specific immunity is the ability to differentiate self and non-self and also react differently to different "aliens", thus mounting an "appropriate" attack. This defense is delayed, that is it requires some time for activation and amplification. It is specific against intruding invader and more effectively aimed at eradication in the event of failure of the first line innate system.

Defense Structure of Immune System

At a macro level, the organs that make up part of the immune system are:

(a)Skin & mucous membranes
(b)Secretions of the body: Tears, Saliva, Mucus, Gastric Juice, Intestinal Juices (Paneth cells of intestinal mucosa secrete protective substances known as alpha-defensins)
(c)Clusters of Lymphoid Tissue: Lymph Nodes, Tonsils & other similar aggregates
(d)Other organs: Spleen, Liver and Bone Marrow

At a micro level, the entities that play a role in the immune system are: (a)White Blood Cells: Neutrophils, Monocytes, Lymphocytes
(b)Tissue Cells: Dendritic cells, Macrophages, Natural Killer cells (NK cells), Lymphocytes (in tissues)
(c)Lymphocytes (those in tissues) are of two principle types:

a.B-Lymphocytes (transform into Plasma Cells which synthesize and secrete antibodies) b.T-Lymphocytes:

There are several different types of T-lymphocytes viz. T-regulator (Tr), T-helper (Th), T-suppressor (Ts), T-cytotoxic (Tc) and serve different functions in the body. T-helper cells, also called CD4+ cells) are further divided into subtypes - Th1, Th2, etc. Collectively, T-lymphocytes modulate and regulate and archive immune processes.

(d)Complement ( a series of proteins which, due their sequential action, causes lysis of the bacterial cells)
(e)Antibodies (Immunoglobulins)
(f)Cytokines are chemicals that are released by immunized activitated cells and serve to modulate or amplify the immune system's processes) eg. Interferon, Interleukins, TNF-a, etc.

Cells involved in the Body Defense

Phagocytic cells (Neutrophils, Macrophages). They are like heavy weapons. These cells kill and digest the foreign invaders (organisms)

Natural Killer Cells (NK cells). The are like soldiers. These cells kill foreign cells, and virus infected cells Complement proteins. They are like small weapons. The are present in blood plasma, they initiate inflammation and facilitate killing of microorganisms and other cells

Cytokines are like guns produced by killer cells (modulate adaptive immune system)
T- and B-Lymphocytes are responsible for cell-mediated response, produce antibodies and cytokines, are like weapon factories
T-cells differentiate into "memory" cells which retain the "memory" of the "alien"; thus, their response is faster during the next encounter.

Cytokines

Cytokines are low-molecular weight proteins synthesized and secreted by immune cells and act on other near-by immune cells, thus amplifying the immune reaction. In keeping with the inherent efficiency of the immune processes, cytokines are not synthesized and stored; they are synthesized when they are required by the body and that too in very small quantities. They are secreted in minute quantities for very brief period of time.

The actions of the cytokines can be clustered into the following major classes: Modulate inflammation

1. Induce activation of immune cells
2. Induce maturation of white or red blood cells
3. Inter-cellular communication between immune cells

Functional Components of the Immune System in IBDasdasd

A brief description of the interplay of the immune processes in the normal scenario and in IBD is explained below:

The exposure of the human gastrointestinal mucosa to bacteria is constant. This A brief description of the interplay of the immune processes in the normal scenario and in IBD is explained below: The exposure of the human gastrointestinal mucosa to bacteria is constant. This colonization is “screened” and “processed” by some of the cells of the immune system and cleared by other mediators. Cells such as the dendritic cells (DC);process the microorganism and “introduce” the microorganism to the T-lymphocytes by “presenting” the proteins (antigens) of the microorganism. Thus, the dendritic cells are also called Antigen-Presenting Cells (APC). Another cell that belongs to the category of APC is the macrophage, which develops from circulating monocytes when they migrate into the tissues in response to inflammation. These APCs, together, are sources of several proinflammatory chemicals viz., (i) Tumor Necrosis Factor-α (TNF-α) (ii) Interleukin- 1ß (IL-1-ß), (iii) Interleukin-6 (IL-6), (iv) Interleukin-12 (IL-12), (v) (IL-23). Another proinflammatory chemical involved is Nuclear Factor-ß(NF-ß.

The Antigen-Presenting Cells also secrete a group of chemicals called Chemokines which serve to attract other inflammatory cells to the site. This interaction of the Antigen- Presenting Cells and T-helper cells (CD4+) cells takes place in the lymphoid tissue of the intestinal wall and the lymph nodes draining the intestines. The DC also secrete Transforming Growth Factor-beta (TGF-ß) and Interleukin-10, both of which create the appropriate environment for the subsequent release of cytokines from the CD4+ cells explained below.

Based on this “presentation ceremony”, the CD4+ cells produce and release the following cytokines: (i)TGF-ß, (ii) Interleukin 1, 4, 6, 12(IL-1, IL-4, IL-6, IL-12), (iii) Interferon- gamma(IFN-γ). These cytokines promote differentiation of various sub-groups of CD4+ cells into T-reg, Th1, Th2 & Th17, the latter three being important for defense against pathogens. These 4 cell types in turn release cytokines which, through the systemic circulation, amplifies the immune potential by activating the effector T-cells and making them “intestine-specific” by inducing development of certain surface proteins. This “enterotropic” integrin enables the cells to move out of the circulation and “home-in” to the to the mucosa where it protects the mucosa from microorganisms.A summary of these interactions and effects is summarized in the figure below:

Role of TNF- alpha:

While the immune mechanisms have the potential to safeguard the intestines against entry of pathogens, an exaggeration of the same mechanism can lead to excessive inflammation and tissue damage. That is what happens in IBD.

While numerous immune and inflammatory processes get enhanced and exaggerated in IBD, all these excesses ultimately result in the following two manifestations:

1. Excessive production of cytokines (TNF-a and others listed before) amplifying immune processes
2. Excessive production of chemokines attracting pro-inflammatory cells amplifying inflammation processes

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