william tarnow-mordi professor of neonatal medicine university of sydney

The Intravenous Immunoglobulins: Current and

Future Role in the NICU Could IVIG be neuro-protective?

William Tarnow-MordiProfessor of Neonatal Medicine

University of SydneyWestmead Hospital and The Children’s

Hospital at Westmead

OFF LABEL DISCLOSURE

William Tarnow-Mordi has documented that his presentation involves comments or discussion of unapproved or off-label, experimental or investigational use of

(a) polyclonal intravenous immunoglobulin (IVIG)

(b) Veronate (anti-staphylococcal immunoglobulin)

DISCLOSURE STATEMENT

Dr. William Tarnow-Mordi has documented that he has nothing else to disclose.

MISSION STATEMENT

The primary aim of clinical studies in the newborn is to identify interventions that increase disability-free survival, employing the most reliable evidence from RCTs.

OUTLINE

Current role of IVIG

(a) Immunomodulatory properties of IVIG

(b) Thrombocytopenia

(b) Haemolytic disease

(c) Infection

Future potential role of IVIG

Is IVIG neuro-protective in newborns with, or at risk of, infection?

Future role of IVIG

1. Do neonatal infections remote from the brain, including CONS, cause brain damage?

2. Are white matter damage and periventricular leukomalacia partly immune-mediated?

3. Is multiple sclerosis (and its animal model) a model for PVL?

4. Can IVIG promote re-myelination in multiple sclerosis and other CNS inflammatory states?

5. Can we do trials big enough to test reliably if

IVIG is neuro-protective in newborns with, or at risk of, infection?





(c) Infection

Pro-inflammatory• opsonic activity

• fixation of complement

• antibody dependent cytotoxicity

• neutrophil chemiluminescence

• phagocytosis

• release of stored neutrophils

““The phagocytes won’t eat the The phagocytes won’t eat the microbes unless the microbes microbes unless the microbes are nicely buttered for them. are nicely buttered for them.

Well, the patient manufactures Well, the patient manufactures the butter himself alright, but the butter himself alright, but

my discovery is that the my discovery is that the manufacture of that butter, manufacture of that butter,

which I call OPSONIN, goes in which I call OPSONIN, goes in the system by ups and down.the system by ups and down.

There is at the bottom only one There is at the bottom only one genuinely scientific treatment genuinely scientific treatment for all diseases, and that is to for all diseases, and that is to

stimulate phagocytosis”.stimulate phagocytosis”. Dr Ridgeon Dr Ridgeon

The Doctor’s DilemmaThe Doctor’s DilemmaG B Shaw 1909G B Shaw 1909

Anti-inflammatoryDown-regulation of inflammatory cytokines via

• Fc receptor blockade, • provision of anti-idiotype antibodies• interference with activation of

– T-cells – B-cells – the cytokine network– complement

Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin.

Kazatchkine MD,. et al. N Engl J Med 2001





(c) Infection

Neonatal alloimmune/ autoimmune thrombocytopenia

• Incidence 1 per 1000

• First reports of IVIG in 1980s

• No RCTs

Immune-mediated thrombocytopenia (Idiopathic thrombocytopenia - ITP)

• Extremely rare in newborns

• First reports of IVIG in 1981

• Subsequently effective in RCTs

• FDA approved





(c) Infection

IVIG for Rhesus disease and ABO incompatibility:Two systematic reviews of the same data

1. Alcock GS, Liley H. Cochrane Review 2002

2. Gottstein R, Cooke RW. Arch Dis Child Fetal Neonatal 2003

In 3 RCTs in 199 infants, IVIG led to• Fewer exchange transfusions

– Relative Risk 0.28 (0.17 – 0.47)

• Shorter phototherapy and hospital stay• No data on disability-free survival

Reduced need for exchange transfusion with IVIG vs standard treatment for haemolytic jaundice:

Number needed to treat 2.7 (95% CI 2.0 to 3.8).

Similar results: differing conclusions

Alcock GS, Liley H. Cochrane Review 2002

‘Well designed studies are needed before routine use of IVIG can be recommended.’

Gottstein R, Cooke RWI. Arch Dis Child Fetal Neonatal 2003

‘IVIG is an effective treatment.’

Mechanisms of action of IVIG in ITP and haemolytic jaundice

• Similar mechanisms are postulated for effects of IVIG in both conditions.

• They are incompletely understood.

Plat

Macrophage

Theory 1: IVIG (Fab portion – fork end) binds sensitised red cells. IVIG Fc portion (fork handle) blocks the Fc receptor on macrophages

Possible mechanisms of IVIG in ITP

Fehr et al, 1982

Theory 2: IVIG upregulates inhibitory FcγRIIB receptors on macrophages. This inhibits phagocytosis.

Macrophage

Plat

?

FcγRIII or IIA

↑ FcγRIIB expression

Possible mechanisms of IVIG in ITP

Samuelsson et al, 2001





(c) Infection

(c) Infection

• Therapeutic IVIG

• Prophylactic polyclonal IVIG

• Prophylactic hyper-immune IVIG (Veronate) to prevent staphylococcal infection

Therapeutic IVIGTwo Cochrane reviews

1. IVIG for treating sepsis and septic shock

Alejandria MM, Lansang MA, Dans LF, Mantaring JBV.

2. Polyclonal IVIG for suspected or subsequently proven infection in neonates

Ohlsson A, Lacy JB.

1. IVIG for treating sepsis and septic shock Alejandria MM, Lansang MA, Dans LF, Mantaring JBV.

Polyclonal IVIG reduces mortality in all age groups combined

n=492

Relative Risk 0.64 (0.64 – 0.80)

p = 0.00009

1. IVIG for treating sepsis and septic shock Alejandria MM, Lansang MA, Dans LF, Mantaring JBV.

1. IVIG for treating sepsis and septic shock Alejandria MM, Lansang MA, Dans LF, Mantaring

JBV.

• No mortality reduction with anti-cytokine or monoclonal IVIG

• Anti-cytokine IVIG (4 RCTs, n =4,318)– RR=0.93; 95% CI 0.86 to 1.01); NS

• Monoclonal IVIG (5 RCTs, n= 2,826)– RR=0.97; (95% CI 0.88 to 1.07); NS


Ohlsson A, Lacy JB. Cochrane Review 2004

mortality reduced in suspected infection, but with borderline statistical significance

n = 318; Relative Risk 0.63 (95% CI; 0.40 - 1.00); p = 0.05

mortality reduced in subsequently proved infection, but with wide confidence interval

n = 262; Relative Risk 0.55 (95% CI 0.31, 0.98); p = 0.04


Ohlsson A, Lacy JB. Cochrane Review 2004

• Insufficient evidence for routine IVIG.

Well-designed trials to assess long term disability and cost effectiveness are needed.

• One such trial is the International Neonatal Immunotherapy Study.

(c) Infection




Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants

Ohlsson A, Lacy JB. Cochrane Review 2004.

• 16 RCTs of IVIG versus placebo or no intervention • ~ 5,000 infants < 37 weeks gestation or <2500 g

• 3-4% reduction in sepsis or serious infection

Cumulative meta-analysis: IVIG vs Placebo or No Treatment

Relative Risk 0.82 (95% CI 0.74-0.92) Risk Difference 0.04 (95% CI 0.02, 0.06)

Polyclonal IVIG prophylaxis

• Reduces infection by 3-4% – statistically significant– marginal clinical significance

• No reductions in mortality, or– NEC, IVH – hospital stay

• No short term serious side effects

• Inconclusive on disability-free survival

Conclusions

• No further RCTs of standard IVIG to prevent infections

• Basic scientists and clinicians should pursue other avenues

(c) Infection




Veronatedata courtesy of Dr Seth Hetherington

• Intravenous Immune globulin

• Donors selected for high titers to:– Clumping factor A – S. aureus – Serine-aspartate repeat G protein – S.

epidermidis

• Antibodies block attachment of bacteria to fibrinogen

Prophylactic hyperimmune anti-staphylococcal IVIG (Veronate): 2017 infants Bwt 500- 1250 g

Blood Stream Infection Control Veronaten = 989 n = 994

Staph aureus 5% 6%

Probable CONS 16% 15%

Definitive CONS 9% 11%

Any Infection 35% 35%

Mortality 7% 6%

Veronate

No difference was statistically significant

Including these data may not alter the result of the meta-analysis of prophylactic trials:~ 3-4% reduction in sepsis with prophylactic IVIG

Too early for data on disability-free survival

Current use of IVIG in the NICU

• Based on promising, but incomplete, evidence of effectiveness in – Thrombocytopenia– Haemolytic jaundice– Neonatal sepsis

with no evidence of its long-term effects.

Future role of IVIG



Leviton, Gillies, Neff, Yaney 1976

White matter damage, or perinatal telencephalic leuco-encephalopathy (PTL), was more common after gram negative septicaemia.

‘It is hypothesized that endotoxin from bacteria adversely affects developing white matter…’

Stoll et al (JAMA) 2004

Stoll, Hansen, Adams-Chapman, Fanaroff, Hintz, Vohr, Higgins, for the NICHD

Neonatal Research Network, JAMA 2004

• 6093 infants < 1000 g bwt assessed at 18 – 22 months corrected for gestation

Neuro-developmental Impairment (NDI) in infected versus uninfected infants

Category N (%) NDI (unadjusted)

OR for NDI adjusted for 21 risk factors

uninfected 2161 (35) 29% -Culture neg clinical infection

1538 (25) 43% 1.3 (1.1-1.6)

Culture positive sepsis

1922 (32) 48% 1.5 (1.2 – 1.7)

Sepsis and NEC

279 (5) 53% 1.8 (1.4 – 2.5)

meningitis 193 (3) 48% 1.6 (1.1 – 2.3)

Neuro-developmental impairment in infants with different pathogens versus uninfected infants

Category N % NDI (unadjusted)

Adjusted OR for NDI relative to uninfected

uninfected 1976 29% -CONS 853 44% 1.3 (1.1 – 1.6)

Other Gm pos

256 48% 1.7 (1.2 – 2.3)

Gram negative

185 45% 1.8 (1.2 – 7.6)

Fungal 96 57% 1.4 (0.9 – 2.2)

After adjustment for antenatal, perinatal and postnatal factors

Neonatal infection, including CONS and culture-negative sepsis, was associated with increases of 30 – 80% in the odds of

• poor head growth (< 10th centile) at – 36 weeks– 18-22 months

• neuro-developmental impairment at 18-22 months

• CONS– although less clinically severe– may be associated with more disability than

any other pathogen (n=853)

• Culture-negative clinical infection – potentially more important than CONS in its

association with disability (n=1538)

Association or causality? RCTs are needed to prove cause and effect

• Neonatal infection may – cause neuro-developmental impairment, or– share a common cause with NDI

• If RCTs (e.g. of IVIG) in neonatal infection – show a reduction in disability– this would confirm infection as causal.

Association between cerebral palsy and coagulase-negative staphylococci.

Mittendorf et al. Lancet 1999

• Cultured amnion-chorion space in 107 preterm infants.

• 35% grew no organisms. 28% grew CONS

• CONS isolated in 4/5 (80%) infants who later manifest CP vs 26/102 (25%) who did not. (p<0.02)

Mittendorf et al. Lancet 1999

• Small study, possible chance association

• Consistent with hypotheses that– CONS may be causal in Cerebral Palsy– mediated by virulence factors such as

haemolysins, deoxyribonuclease, slime and adhesins

Future role of IVIG



Zupan et al, 1996; Volpe, 1997,2001

• Focal, cystic PVL:– more severe, becoming less frequent – progressive loss of all cells in white matter.

• Diffuse PVL – less severe, increasingly frequent– mainly affects developing oligodendrocytes

Nitrosative and oxidative injury to premyelinating oligodendrocytes in PVL

Haynes RL, et al. J Neuropathol Exp Neurol 2003

Autopsied 17 PVL cases and 28 non-PVL controls.

Diffuse PVL involves injury to premyelinating oligodendrocytes through

– activation of microglia – release of reactive oxygen and nitrogen species

Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant.

Damman O, Leviton A. 1998

Remote infection could

– lead to an inflammatory response that may be responsible for initiating and prolonging tissue injury

– induce white matter damage by molecular mechanisms, especially cytokines.

.

Fetal / neonatal cytokinemia and white cell activation in WMD

Duggan et al, Lancet 2001

50 infants 23-29 weeks gestation: cord blood

- for cytokines

- CD45RO T lymphocytes (to assess T cell

activation)

Brain MRI done at median 2 days after birth

• 18 (36%) had cerebral lesions associated with

• ↑ cytokines and % activated T cells

Duggan et al, Lancet 2001

Immune cells might be directly involved in injury

Activated CD45RO+ T lymphocytes express

– activation, homing and adhesion molecules– migrate into tissues – induce apoptosis

The Toll-like receptor TLR4 is necessary for LPS induced oligodendrocyte injury in the CNS

Lehnardt et al. J Neuroscience 2002

To exert its pathogenic effect, LPS requires TLR4, a receptor present on

– circulating monocytes/ macrophages – other systemic immune cells– microglia in the CNS.

LPS (endotoxin) kills oligodendrocytes only when microglia are present in culture

The Toll-Like Receptor TLR4 Is Necessary for Lipopolysaccharide- induced Oligodendrocyte Injury in CNS

Lehnardt et al 2002

Provides a mechanism of action between

(1) LPS (and other microbial antigens)

↓

(2) induction of innate, non-specific immunity

↓

(2) injury to oligodendrocytes and myelin

(as in PVL and multiple sclerosis).

Histological appearance of Multiple Sclerosis

• Demyelination of nerve axons, mostly in white matter, with acute focal inflammatory changes.

• Lesions include – axonal loss– spontaneous re-myelination– multifocal sclerotic plaques.

Spontaneous remyelination in Multiple Sclerosis Perier O, Gregoire A. Brain 1965.

Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis

Chang et al NEJM 2002

Oligodendrocyte progenitor cells characterized in

– developing brain– normal adult human brain– chronic lesions of multiple sclerosis.

Spinal cord axons in the healthy mouse

Normally myelinated axons.

Spinal cord axons after infection with Theiler’s murine encephalo-myelitis virus (TMEV)

• Extensive demyelination

• Some spontaneous remyelination.

• Macrophages/ microglia with ingested myelin debris (arrows).

Recruitment of T lymphocytes across Blood Brain Barrier endothelium in MS and TME Virus infection

Engelhardt J Neural Transmission 2006

Remyelination by oligodendrocytes stimulated by antiserum to spinal cord.

Rodriguez, M. J Neuropathol Exp Neurol. 1987

• Produced anti-serum from mice immunized with homogenized spinal cord (SCH).

• Anti-serum increased remyelination 10 fold in spinal cords after infection by TME virus.

Human monoclonal antibodies reactive tooligodendrocytes promote remyelination in a model

of multiple sclerosis

Warrington et al PNAS 2000

Experiments with human remyelination-promoting mAbs in mice using normal human IVIG (IgG) as control

Spinal cord axons in the healthy mouse

Normally myelinated axons – not infected with TMEV.

Spinal cord axons after chronic infection with Theiler’s murine encephalo-myelitis virus

• Extensive demyelination

• Some spontaneous remyelination.

• Macrophages/ microglia with ingested myelin debris (arrows).

Partial remyelination after infection with TME virus + treatment with monoclonal IgM

Significantly greater remyelination after treatment with monoclonal IgM

Same magnification

Effect of IVIG on remyelination in mouse spinal cord after TME Virus infection


Treatment Group % Oligodendrocyte remyelination

P value

Controls 6.7 -

After human IVIG IgG

14.2 <0.05

After

Human IgM mAB

23.2 <0.001




% OL remyelination in mice was increased

– twofold with human IgG– fourfold with human IgM.



Warrington et al PNAS 2000 Human remyelination-promoting mAbs

• may be a simple, effective therapy.

• can be produced free of infectious agents

• may alleviate the high cost of IVIg.

• may simplify investigation of mechanisms of immunomodulatory therapies.

Anti-apoptotic signaling by a remyelination-promoting human antimyelin antibody

Howe CL Neurobiol Dis 2004

In mice with TMEV, a recombinant hman monoclonal anti-myelin antibody

– induced anti-apoptotic signaling in premyelinating oligodendrocytes and

– reduced caspase-3 activation and caspase gene expression


Howe CL, Neurobiology of Disease; 2004

Polyreactive autoantibodies that trigger repair within demyelinated lesions marked an important shift in our understanding of the role of antibodies in the CNS.

Recombinant monoclonal human IgM autoantibody rescued a pre-myelinating oligodendrocyte cell line from death induced by either hydrogen peroxide or TNF-a.


Howe CL, Neurobiology of Disease; 2004

One mechanism by which IVIG may promote remyelination in CNS inflammatory conditions is by

– binding oligodendrocyte progenitors and

– preventing them from undergoing death induced by H2O2 of TNFα.

CD54+ lymphocytes expressing ICAM-1 in blood from patients before and after IVIG

Créange et al. J Neuroimmunol 2003

Cytokine expression by CSF monocytes in patients with Post Polio Syndrome after IVIG.

Gonzalez J Neuroimmunol 2004

↓ TNF-α (p < 0.05)

↓ IFN-γ (p < 0.001)

• Is clinical evidence consistent with in vitro and in vivo laboratory evidence?

Cochrane Reviews of IVIG in neurological

inflammatory conditions Condition No. of

patientsEffect

Multiple sclerosis 168 ↓ relapses (by 38-74%)

Guillain Barre syndrome 75 speeds recovery

Multifocal neuropathy 34 ↑ strength

Myasthenia Gravis 60 inconclusive

Chronic demyelinating inflammatory polyneuropathy

170 ↓ disability

IVIG for the treatment of relapsing-remitting multiple sclerosis: a meta analysis.

Sorensen PS, Fazekas F, Lee M. Eur J Neurol 2002

Achiron et al; Arch Neurol 2004


Placebo controlled RCT of IVIG vs saline within 6 weeks of first signs of MS in 91 patients

36% lower probability of developing clinically definite multiple sclerosis –

– Risk ratio, 0.36

– 95% CI; 0.15- 0.88

– p = 0.03.


The IVIG group had fewer MRI lesions at 12 months

– reduced volume T2-weighted (P =0.01)– fewer T2 weighted (P =0.01) of – reduced volume of gadolinium enhancing

lesions (P=0.03) .


Future studies evaluating the combined effects of

– IVIG – interferons– glatiramer acetate

may offer additional benefit on the occurrence of second attack.

These studies suggest that, in animals and adult humans, IVIG can reduce cerebral inflammation and ameliorate pre-existing cerebral lesions.

3. Is multiple sclerosis a model for PVL?




An ideal RCT to test if IVIG increases disability-free survival should

• randomise neonates to prophylactic, repeated IVIG or placebo.

• be large enough to detect realistically moderate differences with adequate power

• include long term follow up of – neuro-developmental and cognitive outcomes.

International Neonatal Immunotherapy Study, INIS

[Google] npeu inis

www.npeu.ox.ac.uk/INIS.htm

(downloadable copy of this talk will be available)

http://www.npeu.ox.ac.uk/INIS.htm


A randomised placebo controlled trial of IVIG in proven or suspected neonatal sepsis

– Revised sample size 4,000 – to yield 90% power to detect a 5% risk

difference in death or major disability


– 2 doses of 500 mg/ kg (total dose of 1 g/kg )– as an adjunct to antibiotic treatment

It does not therefore fulfil all the criteria for an ideal test of these hypotheses.

However, …

Two multi-centre trials that provided more sustained doses of IVIG, for 2 weeks of more, have already been done, in a total of over 4,000 patients.

• 2416 infants < 72 hr after birth– stratified according to birth weight – (501-1000 g and 1001-1500 g)

• randomly assigned to fortnightly – prophylactic IVIG (n = 1204) or – control (n = 1212).

• Prophylactic IVIG failed to reduce the incidence of hospital-acquired infections.

• These were 208 (17.3%) in the IVIG group and 231 (19.1%) in the control group

• (Relative Risk, 0.91; 95 percent confidence interval, 0.77 to 1.08).

Prophylactic hyperimmune anti-staphylococcal IVIG (Veronate): 2017 infants Bwt 500- 1250 g

Blood Stream Infection Control Veronaten = 989 n = 994

Staph aureus 5% 6%

Probable CONS 16% 15%

Definitive CONS 9% 11%

Any Infection 35% 35%

Mortality 7% 6%

Speculation

It would be valuable to determine the rates of neuro-developmental impairment in these randomised cohort, or subsets within them

To test the hypothesis that sustained IVIG therapy is (a) safe, (b) neuro-protective in neonates at risk of sepsis.

Conclusions

Modulation of inflammation is a relatively new strategy for preventing or treating neurological injury.

New evidence is needed to evaluate IVIG as a non-steroidal anti-inflammatory agent that may reduce neonatal mortality and morbidity.

Sir Richard Doll and Sir Richard Peto

Sir Richard Doll Sir Richard Doll Controlled trials: the 1948 watershed Controlled trials: the 1948 watershed

BMJ 1998: 317: 1217-20BMJ 1998: 317: 1217-20

• “Early randomised trials (1940s) can properly be criticised on the grounds that they were often too small to have any chance of detecting moderate effects.

• “Small trials can be successful when the effect is large but this seldom occurs.“

• “Only in the 1980s did it become possible to organise the groundbreaking international study of infarct survival (ISIS) trials…

• in tens of thousands of patients, which showed the value of moderate improvements in the treatment of common diseases.”

The ISIS 1 Trial

• Atenolol infusion vs placebo after heart attack

• 16,000 patients recruited

• Showed a 2% mortality reduction- from 13% to 11%

The ISIS 2 Trial

• Aspirin vs placebo after heart attack

• 17,000 patients recruited

• Showed a 23% mortality reduction- from c. 11% to 8%.

The Goddess of Chance is a capricious mistress. Yet, with large enough numbers, she becomes our obedient servant – yielding up the truth.

Anon.

Sample sizes to show Sample sizes to show moderate moderate or or largelarge differences differences in disability-free survival with 90% power at 2p = 0.05in disability-free survival with 90% power at 2p = 0.05

Adverse outcome in controls [C]%

Adverse outcome in treated group [T]%

Absolute risk difference

[C-T] %

Total sample needed (both groups combined)

Number needed to treat (NNT) to prevent one case

42 40 2 20, 712 50

42 39 3 9, 168 33

42 38 4 5,134 25

42 37 5 3,270 20

42 32 10 800 10

• If newborns are to benefit from evidence as reliable as in cardiology,

• much larger numbers are needed–i.e. thousands, not hundreds

A challenge

Judged by whether sufficient evidence exists to exclude moderate benefits or harms, most current perinatal treatments remain inadequately evaluated.

A solution

• Samples of thousands, not hundreds, where the research question merits it

• Multicentre, international collaboration

• Prospective meta-analysis

• Simple, inexpensive modes of follow up

Prospective meta-analysis

– Multiple trials with same design + hypotheses– Pledged to combine their results in a single, individual

patient based meta-analysis– New trials and hypotheses can be added before any

results are known– Avoids publication bias, data driven hypotheses– Combines the methodological advantages of a single

trial with pragmatic benefits of flexible funding arrangements and recognition needs of different national agencies

International neonatal oxygen trials: NeoProm prospective meta-analysis

co-ordinator: Lisa Askie

Australia – 1200 – NHMRC*NZ - 300 – HRC*UK - 1200 – MRC*Canada- 1200 - CHIR*US - 1500 – NICHD US POSTUS - 1300 - NICHD SUPPORT*

*Already funded. Possible total = > 6,000

Acknowledgments

PanelistsCarol J. Baker, Baylor College of Medicine, Houston, TXBarbara J. Stoll, Emory University School of Medicine, Atlanta, GALeonard E. Weisman, Baylor College of Medicine, Houston, TX

Further acknowledgments

Alan Leviton, Arne Ohlsson, Olaf Damman, Peter Brocklehurst, Khalid Haque, David Isaacs, Wendy Hague, John Simes, Barbara Farrell, Priya Duggal-Beri, Ann Cust, David Henderson-Smart, Ben Stenson, David Edwards, Ryszard Lauterbach, Seth Hetherington, Amy Morris, Iain Chalmers, The Cochrane Collaboration and the hundreds of parents, babies, nursing and medical staff in over 100 hospitals worldwide who are contributing to the International Neonatal Immunotherapy Study (INIS) of polyclonal IVIG.

William Silverman (‘Fumer’) 1917-2004

Taught his students and friends

• to consider the long term consequences of neonatal care, for patients and families

• to cultivate a habit of lifelong (un) learning

• ‘semper plangere’ (always complain) - and look for better evidence

william tarnow-mordi professor of neonatal medicine university of sydney

Documents

reports of ivig

cells b

inflammatory diseases

inflammatory cytokines

intravenous immunoglobulins

multiple sclerosis

intravenous immune globulin

william tarnowmordiprofessor