1. Co-receptors deliver powerful responses Risk of triggering strong co-stimulatory signals Mice are not humans

2. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. Suntharalingam GSuntharalingam G, Panoskaltsis N.Panoskaltsis N N Engl J Med. 2006 Sep 7;355(10):1018-28. Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, (pain in multiple muscles) nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti- interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine-release syndrome, all six patients survived. Documentation of the clinical course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease.

3. „Extreme response The drug, an antibody called TGN1412, is being developed by a German company TeGenero with the aim of directing the immune system to fight cancer cells, or calm joints inflamed by rheumatoid arthritis. The antibody binds to a receptor molecule called CD28 on the surface of the immune system's infection- fighting T cells. (Nature March 17 2006) Scientists who work in the field say there are several possible ways that the drug could have triggered multiple organ failure. It may have stimulated T cells so much that they released an overwhelming flood of inflammatory molecules called cytokines. Or perhaps T cells launched an attack on the body's own tissues, ignoring the safety mechanisms that normally keep this in check. Modulation of the CD28 co-stimulatory pathway.

4. Development of lymphoid organs

5. Lymphocyte trafficing

6. The Immune response

7. Dendritic cell movie here

8. Phases of T cell response (review)

9. TCR CD4 Naive CD4+ T cell Th0 blaszt TCR CD4 TCRTh1 Intracelluláris patogén Gyulladás Tc aktiváció IgG1 & IgG3 ellenanyag ADCC, opszonizáció Komplement aktiváció TCR CD4 Th2 Extracelluláris patogén Soksejtek parazita Szekretoros IgA IgE, allergia TCR CD4 Treg Th1 gátlás Tolerancia fenntartása KLONÁLIS OSZTÓDÁS DIFFERENCIÁCIÓEPIGENETIKAI VÁLTOZÁS, MEMÓRIA VÁLTOZÁS, MEMÓRIA KÖLCSÖNHATÁSAKTIVÁCIÓINSTRUKCIÓ Th17 Extracelluláris patogén Gyulladás Autoimmun betegségek Allergia TCR CD4 EFFEKTOR HELPER T-CELLS DC

10. The germinal center reaction

11. The dendrites of follicular dendritic cells use complement receptors to take up intact pathogens and antigens and preserve them for long periods.

12. After somatic hypermutation, centrocytes with high-affinity receptors for antigen are rescued from apoptosis.

13. B cell Helper T cell IL-2 IL-4 IL-5 B cell proliferation and differentiation – isotype switch IL-2 IL-4 IL-5 IgM IgG IgA IgE IL-2 IL-4 IL-6 IFNγ IL-5 TGFβ IL-4 REGULATION OF ISOTYPE SWITCH OF B CELLS

14. EFFECTOR FUNCTIONS OF ANTIBODIES 1)Neutralisation 2)Opsonization (facilitated phagocytosis) 3)ADCC 4)Complement activation ( see it later )

15. NEUTRALISATION

16. OPSONIZATION An opsonin is any molecule that enhances phagocytosis by marking an antigen for an immune response. In the picture opsonins are antibodies.

17. ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY (ADCC)

18. VACCINATION

19. Methods of immunisation Serum containing the specific antibody (usually IgG) Endagered subject The subject with specific antibody - Does not depend on the immune response of the recipient - Acts immediately - Short-term protection only (elimination of Ig’s!) II. Active immunisation Vaccination is a good example, when not antibodies but inactivated or attenuated pathogens or purified antigens from pathogens are administered sc. Immune response depends on the immune state of the recipient, immune protection needs time to develop, but long term protection is provided (memory cells). I. Passive

20. PASSZÍV IMMUNIZÁLÁS No activation of the immune system Acts immediately The protection is short-term only Elimination of Immunoglobulins Pooled intravenous immunoglobulin (IVIg) (Intratect, Intraglobin, Octagam, Gammagard) (approx. 59% IgG1, 36% IgG2, 3% IgG3, 2% IgG4 and maximally 5% IgA) PROTECTED SUBJECTS serum antibodies ENDANGERED SUBJECT Intravenous immunoglobulin

21. Intravenous immunoglobulin #1 Low dose: passive immunisation Indications: primary or secundary immune deficiency - congenital agammaglobulinaemia - severe combined immune deficiency (SCID) - Wiskott-Aldrich syndrome - multiplex myeloma or chronic lymphoid leukemia - premature babies - allogenic bone marrow transplantation - congenital HIV-infection (AIDS)

22. High dose: immune suppression The „physiologic” immunsuppressive agent! Especially useful in the autoimmune diseases of children, the only limit is the price. Indications: - immune thrombocytopenia (ITP) - dermatomyositis/polymyositis - myasthenic crisis (myasthenia gravis) - Guillain-Barré syndrome - graft versus host reaction (after transplantation) Intravenous immunoglobulin #2

23. Attenuated pathogen Killed pathogen Microbial extract / product Bacterial Diseases Typhoid fever (PO) BCG (M. bovis) Typhoid fever Cholera B. pertussis (DPT) Plague (Y. pestis) Anthrax B. pertussis (DTPa) Diphtheria (Tox.) Tetanus (Tox.) *Meningococcal *Pneumococcal *H. influenzae b Viral Diseases Measles Mumps Rubella Polio (Sabin - PO) Yellow fever Polio (Salk) Hep. A Influenza Rabies Japanese encephalitis Hepatitis B (HbSAg) Vaccine components