Co-receptors deliver powerful responsesRisk of triggering strong co-stimulatory signals

Mice are not humans

Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.

Suntharalingam G, 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.

„Extreme responseThe 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.

Development of lymphoid organs

Lymphocyte trafficing

The Immune response

Dendritic cell movie here

Phases of T cell response(review)

TCR

CD4

Naive CD4+ T cellNaive CD4+ T cell

Th0 blasztTh0 blaszt

TCR

CD4

CD4

TCR

Th1Th1 Intracelluláris patogén GyulladásTc aktivációIgG1 & IgG3 ellenanyagADCC, opszonizációKomplement aktiváció

TCR

CD4 Th2Th2Extracelluláris patogénSoksejtek parazitaSzekretoros IgA IgE, allergia

TCR

CD4 TregTregTh1 gátlásTolerancia fenntartása

KLONÁLIS OSZTÓDÁSKLONÁLIS OSZTÓDÁSDIFFERENCIÁCIÓDIFFERENCIÁCIÓ

EPIGENETIKAIEPIGENETIKAI VÁLTOZÁS, MEMÓRIAVÁLTOZÁS, MEMÓRIA

KÖLCSÖNHATÁSKÖLCSÖNHATÁSAKTIVÁCIÓAKTIVÁCIÓ

INSTRUKCIÓINSTRUKCIÓ

Th17Th17Extracelluláris patogénGyulladásAutoimmun betegségekAllergia

TCR

CD4

EFFEKTOR HELPER T-CELLSEFFEKTOR HELPER T-CELLS

DCDC

The germinal center reaction

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

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

apoptosis.

B cell

Helper T cell

IL-2IL-4IL-5

B cell proliferation and differentiation – isotype switch

IL-2IL-4IL-5 IgM

IgG

IgA

IgE

IL-2IL-4IL-6IFNγ

IL-5TGFβ

IL-4

REGULATION OF ISOTYPE SWITCH OF B CELLS

EFFECTOR FUNCTIONS OF EFFECTOR FUNCTIONS OF ANTIBODIESANTIBODIES

1) Neutralisation

2) Opsonization (facilitated phagocytosis)

3) ADCC

4) Complement activation (see it later)

NEUTRALISATIONNEUTRALISATION

OPSONIZATIONOPSONIZATION

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

AANTIBODY NTIBODY DDEPENDENT EPENDENT CCELLULAR ELLULAR CCYTOTOXICITY YTOTOXICITY (ADCC)(ADCC)

VACCINATION

Methods of immunisationSerum 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 immunisationVaccination 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

PASSZÍV IMMUNIZÁLÁS

No activation of the immune system Acts immediately

The protection is short-term onlyElimination 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

Intravenous immunoglobulin #1

Low dose: passive immunisationIndications: 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)

High dose: immune suppressionThe „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

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