Immunomodulation in Homotoxicology Juan Carlos Herrera Correa, MD

Immunological tolerance Hyporeactivity or non-reactivity of the immune system to an antigen, induced by previous contact with this antigen Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Tolerogenic Reparative IL 10 -TGF

MALT

MALT NALT LALT BALT GALT SALT

Esta en homing 2V. Fig. 2. Gut-associated lymphoid tissues (GALT) and the common mucosal immune system (CMIS). MLN, mesenterial lymph node; TD, thoracic duct; M cell, membranous cell; pIgA, polymeric IgA. Inductive sites in the gut-associated lymphoid tissues (GALT) The gut contains the most abundant lymphoid tissues and includes organized as well as diffuse lymphoid elements. Organized lymphoid tissues are comprised of two units - B-cell follicles and para- or interfollicular T-cell areas - assembled within a matrix of loose connective tissue and follicular DCs. These follicles occur singly or in groups and harbour variable numbers of macrophages and T cells (88). Follicle-dome structures form the main lymphoid component of the Peyer's patches in the jejunum and ileum and are also found in the large intestine, and especially in the appendix. These structures appear to play an important role in the induction of disseminated immune responses to oral vaccines (Fig. 2). Typically, the follicles contain a majority of B cells, approximately half of which are activated. The T-cell zone comprises a majority of CD4+ T cells; CD8+ [alpha][beta] TCR T cells are mainly located in the parafollicular area whereas CD8+ [gamma][delta] TCR T cells are rare. The dome is covered by a specialized epithelium or "follicle-associated epithelium" (FAE), containing antigen-transporting M cells. [Help with image viewing] Fig. 2. Gut-associated lymphoid tissues (GALT) and the common mucosal immune system (CMIS). MLN, mesenterial lymph node; TD, thoracic duct; M cell, membranous cell; pIgA, polymeric IgA. The cecal and colonic mucosae are also variably invested with comparable lymphoid patches, although the epithelium covering these lymphoid aggregates does not show the specializations of M-cell-containing FAEs (89, 90). Clusters of follicles are also found adjacent to the ano-rectal junction (91, 92). The potential importance of the rectal lymphoid tissues as an IgA inductive site and as a source of IgA plasma cell precursors is suggested by several studies. First, the predominance of IgA2 cells over IgA1 cells in the lamina propria of the large intestine clearly diverges from the relative apportioning of the two in other mucosal tissues, such as in the small intestine and in the upper large intestine (93). Further, rectal immunization of humans, non-human primates and rodents has been shown to induce strong secretory antibody responses in the rectal mucosa. Although in most instances, rectal immunization induced secretory antibody responses in the rectal mucosa itself (94-100), in some instances, rectal vaccination could induce specific antibodies in serum, and also in secretions from remote mucosal organs, such as saliva (102), and genital secretions (92-94, 96). Although the potential of the rectal mucosa to serve as site of induction of mucosal responses is now well established, it should be pointed out that rectal immunization of macaques with CT, one of the most powerful mucosal immunogens, was shown to be poorly effective at inducing an immune response in the upper part of the intestine and especially in the small intestine (100). Czerkinsky, Cecil; Anjuere, Fabienne; McGhee, Jerry R.; George-Chandy, Annie; Holmgren, Jan; Kieny, Marie-Paule; Fujiyashi, Kohtaro; Mestecky, Jiri F.; Pierrefite-Carle, Valérie; Rask, Carola; Sun, Jia-Bin. Mucosal immunity and tolerance: relevance to vaccine development. Immunological Reviews. Volume 170 August 1999 pp 197-222.

Mucosa-Associated Lymphoid Tissues Las flechas mas gruesas represntan la migracion principal. Importante el direccionamiento del tracto digestivo a las glandulas mamarias. Brandtzaec trabaja en el laboratorio de inmunopatologia e inmunohistoquimca del instituto de patologia de la univesidad de Oslo. Norway. Brandtzaeg, P. Homing of mucosal immune cells-a possible connection between intestinal and articular inflammation. Alimentary pharmacology & Therapeutics, Supplement. Volume 11 Supplement 3  December 1997 pp 24-39. Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Patients who are allergic to cow’s milk show increased intestinal permeability. Van Elburg RM, Heymans HS, De Monchy JG. Effect of disodium cromoglycate on intestinal permeability changes and clinical response during cow’s milk challenge. Pediatr Allergy Immunol 1993; 4:79–85. Schrander JJ, Unsalan-Hooyen RW, Forget PP, et al. [51Cr] EDTA intestinal permeability in children with cow’s milk intolerance. J Pediatr Gastroenterol Nutr 1990; 10:189–92. Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Immunological tolerance and intestinal mucosa Barrier mechanism: secretion of mucus Intestinal flora Mucosal integrity IgA MALT regulation mechanisms Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Antigen presentation Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Esta en homin B de junio 2003. Mudter, Jonas MD; Neurath, Markus F. MD. Mucosal T cells: mediators or guardians of inflammatory bowel disease?. Current Opinium in Gastroenterology. Volume19(4) July 2003  pp 343-349 Figure 2. Pathogenesis of Crohn's disease: Pro-inflammatory pathways Antigen-presenting cells are activated by luminal antigens and subsequently produce proinflammatory cytokines. Both IL-12 and IL-18 contribute to TH1 differentiation of CD4+ Lamina propria T-cells. On the one hand these cytokines strongly induce TH1 polarisation, on the other hand the transcription factors T-bet and STAT-1 are potent mediators of TH1 differentiation independent from cytokine driven pathways. TH1 lymphocytes itself stimulate macrophages to secrete further proinflammatory cytokines inducing T-cell apoptosis resistance which is conveyed by cytokine-dependent activation of transcription factors, namely STAT-3 and NF[kappa]B. Finally, tissue damage is mediated by the influx of granulocytes and local stroma cells. Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Antigen presentation Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

APC B B Th0 Th3 Th1 Th2 Th1 Antigen IGM, IgE, IgG IGA MHC TCR IL-10 Macrophage CD8 M. Rosales Sdme de Inflamación de las Mucosas. 2nd edition MHC PROCESSED ANTIGEN TCR Th0 IL-10 Th1 Th3 Th2 TGF-B IL-10 IL2, IFN-G, TNF-A IL4, IL5, IL6 IL9, IL10, IL13 37 Secretory IgA antibody response may also be induced through Th1 cytokines (IL-2, IFN-Á) as shown with studies on intracellular pathogens such as salmonella. 35. y parece que el mejor estimulante para la produccion de Iga es el factor de crecimiento. LOS TH2 CONLA PRODUCCION DE IL4 POTENCIAN 1000 VECES LA PRODUCCIONDE IgE EN LOS LINFOCITOS B ESTIMULADOS CON LPS PEQUEÑAS CANTIDADES DE INTERFERON GAMA BLOQUEAN ESTE EFECTO. Th1 B B Cell-mediated immunity Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006 IGM, IgE, IgG IGA

How does the body react to the entry of an antigen? Production of antibodies Anergy or apoptosis Immunological tolerance Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Normal response in CD 4 + T lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Types of response Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Immunological tolerance Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Schmidt-Weber, C. B.; Blaser, K. T-cell tolerance in allergic response. Allergy: European Journal of Allergy and Clinical Immunology. Volume 57(9)  September 2002 pp 762–768 Swiss Institute for Allergy and Asthma Research, Switzerland

Tolerance mechanisms 1. Insufficient co-stimulation Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Without co-adjuvants Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Tolerance mechanisms 1. Insufficient co-stimulation 2 Tolerance mechanisms 1. Insufficient co-stimulation 2. Abundant soluble antigen without adjuvants Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Tolerance mechanisms 1. Insufficient co-stimulation 2 Tolerance mechanisms 1. Insufficient co-stimulation 2. Abundant soluble antigen without adjuvants 3. CTLA4 receptors Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

“Cytolytic T lymphocytes” Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Tolerance mechanisms 1. Insufficient co-stimulation 2 Tolerance mechanisms 1. Insufficient co-stimulation 2. Abundant soluble antigen without adjuvants 3. CTLA4 receptors 4. Slight mutation of antigen structure Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Tolerance mechanisms 1. Insufficient co-stimulation 2 Tolerance mechanisms 1. Insufficient co-stimulation 2. Abundant soluble antigen without adjuvants 3. CTLA4 receptors 4. Slight mutation of antigen structure 5. APC-mediated suppression Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IL 10 Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Tolerance mechanisms 1. Insufficient co-stimulation 2 Tolerance mechanisms 1. Insufficient co-stimulation 2. Abundant soluble antigen without adjuvants 3. CTLA4 receptors 4. Slight mutation of antigen structure 5. APC-mediated suppression 6. Bystander suppression Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Bystander suppression Immunological bystander reaction Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Immunological bystander reaction Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Immunological bystander reaction (IBR) Special kind of “low dose antigen reaction” Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Entry Oral Other routes Mucosa-associated lymphoid tissue MALT Immunological cells of the matrix Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

The potentized proteins of the medicines are immunologically challenged by antigen presenting cells Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Antigen presenting cells IBR Antigen presenting cells APC Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Phagocytosis Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR D1-D14 Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Processing in proteasomes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Digestion by lysosomes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Short sequences of amino acids (9-15) IBR Short sequences of amino acids (9-15) Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Coupling to MHC class II Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Transport via vacuoles Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR To the cell membrane Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Anchorage in glycocalyx Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Expression of epitopes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Patrolling lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR CD4 T lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR APC-lymphocyte complex Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Epitope – Paratope Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR B7 – CD28 Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

As many epitopes as there are compounds IBR As many epitopes as there are compounds Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

As many epitopes as there are compounds IBR D3 D8 D5 D5 D12 As many epitopes as there are compounds Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Cytokine activating co-stimulants IBR Cytokine activating co-stimulants Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Activated T lymphocyte IBR IL2 Activated T lymphocyte Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Regulatory lymphocytes IBR Regulatory lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR TH3 lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Homing Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Cloning of TH3 lymphocytes IBR Cloning of TH3 lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Cloning of TH3 lymphocytes IBR Cloning of TH3 lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Cloning of TH3 lymphocytes IBR Cloning of TH3 lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Cloning of TH3 lymphocytes IBR Cloning of TH3 lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Cloning of TH3 lymphocytes IBR Cloning of TH3 lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Bloodstream and lymph system IBR Bloodstream and lymph system Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Chemotaxis Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Entry into tissues Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Antigenic similarity Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IBR Antigenic similarity Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

TGF-β IBR Antigenic similarity Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IL4 IBR Antigenic similarity Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

IL4 IL10 IBR Antigenic similarity Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Modulation of proinflammatory lymphocytes IBR Modulation of proinflammatory lymphocytes Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Differentiation to IgA producing cells TGF-β IBR IL10 IL4 Differentiation to IgA producing cells Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

Inhibits the activation of macrophages IBR IL10 Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006

APC B B IFN-G IL4 Th0 Thr Th1 Th2 IL 13 Antigen IGM, IgE, IgG IGA MHC PROCESSED ANTIGEN TCR Th0 Th1 Thr Th2 TGF-B IFN-G IL4 IL 13 IL4, IL5, IL6 IL9, IL10, IL 13 IL2, IFN-G, TNF-A 37 Secretory IgA antibody response may also be induced through Th1 cytokines (IL-2, IFN-Á) as shown with studies on intracellular pathogens such as salmonella. 35. y parece que el mejor estimulante para la produccion de Iga es el factor de crecimiento. LOS TH2 CONLA PRODUCCION DE IL4 POTENCIAN 1000 VECES LA PRODUCCIONDE IgE EN LOS LINFOCITOS B ESTIMULADOS CON LPS PEQUEÑAS CANTIDADES DE INTERFERON GAMA BLOQUEAN ESTE EFECTO. B B Cell-mediated immunity Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006 IGM, IgE, IgG IGA

Macrophages Monocytes M cells Epitopes TH3 LT TGFB TH2 TH1 T4 IL4 IL10

Cytokines Fibrolysis IL4 - IL 10 - TGFb TNFa - IFNg – IL1 Fibrogenesis SERPINs SERPS Inhibitors of metalloproteinases of the extracellular matrix Metalloproteinases of the extracellular matrix Dr. Juan Carlos Herrera Correa_Immunomodulation_Speakers' Training 2006