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Co-receptors deliver powerful responses
Risk 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 antiinterleukin-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.
Modulation of the CD28 co-stimulatory pathway.
„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 infectionfighting 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.
Development of lymphoid organs
Lymphocyte trafficing
The Immune response
Dendritic cell movie here
(review)
Phases of T cell response
Th1
EFFEKTOR HELPER T-CELLS
CD4
TCR
CD4
Naive CD4+ T cell
TCR
DC
CD4
CD4
TCR
TCR
Th0 blaszt
CD4
TCR
CD4
KÖLCSÖNHATÁS
AKTIVÁCIÓ
INSTRUKCIÓ
TCR
KLONÁLIS OSZTÓDÁS
DIFFERENCIÁCIÓ
Intracelluláris patogén
Gyulladás
Tc aktiváció
IgG1 & IgG3 ellenanyag
ADCC, opszonizáció
Komplement aktiváció
Th2
Extracelluláris patogén
Soksejtek parazita
Szekretoros IgA
IgE, allergia
Th17
Extracelluláris patogén
Gyulladás
Autoimmun betegségek
Allergia
Treg
Th1 gátlás
Tolerancia fenntartása
EPIGENETIKAI
VÁLTOZÁS, MEMÓRIA
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.
REGULATION OF ISOTYPE SWITCH OF B CELLS
Helper T cell
IL-2
IL-4
IL-5
IL-2
IL-4
IL-5
IL-2
IL-4
IL-6
IFNγ
IL-5
TGFβ
IgM
IgG
IgA
B cell
IL-4
B cell proliferation and differentiation – isotype switch
IgE
EFFECTOR FUNCTIONS OF
ANTIBODIES
1)
2)
3)
4)
Neutralisation
Opsonization (facilitated phagocytosis)
ADCC
Complement activation (see it later)
NEUTRALISATION
OPSONIZATION
An opsonin is any molecule that enhances phagocytosis by marking an antigen
for an immune response. In the picture opsonins are antibodies.
ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY
(ADCC)
VACCINATION
I. Passive
Methods of immunisation
Serum containing the
specific antibody
(usually IgG)
Endagered subject
- Does not depend on the
immune response of the
recipient
- Acts immediately
- Short-term protection only
(elimination of Ig’s!)
The subject with
specific antibody
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).
Intravenous immunoglobulin
PASSZÍV IMMUNIZÁLÁS
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
No activation of the immune system
Acts immediately
The protection is short-term only
Elimination of Immunoglobulins
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)
Intravenous immunoglobulin #2
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)
Vaccine components
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)