CELL-MEDIATED IMMUNITY

T-CELL CYTOTOXICITY

DELAYED HYPERSENSITIVITY

GRANULOMATOUS REACTIONS

PRIMARYREACTION

SECONDARY REACTION

TERTIARY REACTION

ANTIBODY MEDIATED

CELL MEDIATED

Ag+Ab AgAb

in vitro in vivo

INACTIVATION

AGGLUTINATION, LYSIS

OPSONIZATION

PRECIPITATION

MAST CELLDEGRANULATION

NEUTRALIZATION

CYTOLYTIC REACTIONS

IMMUNE COMPLEX

REACTIONS

ANAPHYLACTIC

REACTIONS

+Ag->

T-DTH

T-CTL

LYMPHOKINES

MACROPHAGE ACTIVATION

TARGET-CELL LYSIS

DELAYED

HYPERSENSITIVITYREACTIONS

CELL

DESTRUCTION

BLASTTRANSFORMATION

LEVELS OF REACTIONS OF ANTIGEN WITH ANTIBODY OR CELLS

EFFECTOR T-CELLS

Ab or + INSOLUBLE ANTIGEN GRANULOMA

IgG1, IgG3

COMPLEMENT

FIXING

ANTIBODIES

OPSONIZATION,

PHAGOCYTOSIS

M1 MACROPHAGE

ACTIVATION

B-

CELL

Th1

CTL

INF-γ

INF-γ

IL-17

IL-17CD8+

T Th2

B-CELL

IgG2, IgG4

IgA

ANTIBODY IgE

MAST CELL

DEGRANULATION

NEUTRA-

LIZATION

EOSINOPHILS

DIFFERENTIATION

AND ACTIVATION

INHIBITION

OF

INFLAM-

MATION

(M2 Mϕ)

IL-4,

-10, -13

IL-4

Il-13

IL-5

CD4+

T-CELL

ANTIGENIC STIMULUS

Th2 – VASCULAR EFFECTS

SECRETORY ANTIBODY

Th1 – DIRECTED TO CELLULAR

RESPONSES, Antibody & CMI

CD4+

T

DELAYED

HYPERSENSITIVITY

TYPE I TYPE II

Th17

INF-γ

TNF

T-CELL CYTOXICITYCONTACT DERMATITIS

SMALL POX

MEASLES

INFLUENZA

GRAFT VS. HOST

GRAFT REJECTION

PSORIASIS

ALOPECIA

CHRONIC HEPATITIS

CROHN DISEASE

POLYMYOSITIS

TUMOR IMMUNITY

MONOCLONAL ANTIBODY TREATMENTS

CD4 AND CD8 KILLER CELLS

CD 8 KILLER T-CELL

CULTURED CELLS

ALONE DAY 1 DAY 3

PLUS T-CTL DAY 1 DAY 3

ANOIKIS

CELL DEATH WHEN ANCHORAGE DEPENDENT CELLS

SEPARATE FROM BASEMENENT MEMBRANE

AND EACH OTHER

NICKEL

DERMATITIS

POISON

OAK

CONTACT

DERMATITIS

NORMAL SKIN CONTACT DERMATITIS

CONTACT

DERMATITIS

INCREASED

LYMPHOCYTES IN

DERMIS

LYMPHOCYTES

IN EPIDERMIS

ALLERGIC CONTACT DERMATITIS

400X400X

200X40X

SMALLPOX

VACCINATION

SMALLPOX

Primary skin and mucous membrane

Lesions

Death 1. Hemorrhage into the skin

2. Pneumonia due to seconday

infection with Strep

MacCallum, WC. Textbook of Pathology

B. Saunders, Co.

Philidelphia 3rd Ed 1924

Viral exanthum

TAKE

MEASLES

RASH IS CAUSED BY T-CTL OF INFECTED SKIN CELLS

VIRAL EXANTHUM MEASLES PNEUMONITIS

MEASLES

SIMILAR COURSE IN

FLU AND COVID-19,

BUT THESE INFECT

BRONCHIAL

EPITHELIUM

INFLUENZA AND SARS COVID-19

INFLUENZA/COVID-19 VACCINES

THREE LEVELS OF PROTECTIVE IMMUNITY

1. ANTI-VIRUS 2. ANTI-CELL MEMBRANE 3. T-CTL

Marcia A. Blackman

Trudeau Institute

Ian Guest

Wadsworth

Erik Brinks

U. Minnesota

David Woodward

Keystone Symposia

Richard Dutton

U. Massachusetts

Suzy Swain

U. Massachusetts

Tara Strutt

U. Massachusetts

Kai McKinstry

U. Massachusetts

Sell S, Guest I, McKinstry KK, Strutt TM, Kohlmeier, JE, Brincks E, Tighe M, Blackman, MA, Woodland DL, Dutton RW,

Swain SL. Intraepithelial T-cell cytotoxicity, induced bronchus associated lymphoid tissue (iBALT) and proliferation of

bronchial epithelium in experimental mouse models of influenza. Viral immunology 2014; 27(10):484-496.

DOI: 10.1089/vim.2014.0077

Stewart Sell

Wadsworth

Jacob Kohlmeier

Emory U.

Mike Tighe

Trudeau Institute

IMMUNOPATHOLOGY OF MURINE MODELS OF EXPERIMENTAL

INFLUENZA

EPITHELIAL

CELLS

TYPE II

PNEUMOCYTES

TYPE I

PNEUMOCYTES

TERMINAL

BRONCHIOLE

EXPERIMENTAL INFLUENZA INFECTION OF MOUSE LUNG

IMMUNPEROXIDASE STAIN FOR VIRUS

MEMORY T 200x MEMORY T 400x

NAÏVE 200x NAÏVE 400x

ANTI-FLU VIRUS

NORMAL – NOT INFECTED FLU INFECTED – DAY 8

GOBLET CELLS

BASEMENT

MEMBRANE

LYMPHOCYTES

ARTERY

Sell S, Guest I, McKinstry KK, Strutt TM, Kohlmeier, JE, Brincks E, Tighe M, Blackman, MA, Woodland DL, Dutton RW, Swain

SL. Intraepithelial T-cell cytotoxicity, induced bronchus associated lymphoid tissue (iBALT) and proliferation of bronchial

epithelium in experimental mouse models of influenza. Viral immunology 2014; 27(10):484-496. DOI: 10.1089/vim.2014.0077

Br

H&E

BRONCHIAL EPITHELIUM AND TYPE II PNEUMOCYTS

INFILTRATED BY CD4 MEMORY T-CELLS – DAY 8

CD3 CD3

EXPERIMENT 3. TRANSPLANTATION OF CD4 MEMORY

CELLS TO SCID MICE PARTIALLY PROTECTS.

ALSO NUDE AND JHD RECIPIENTS.

NUDE – T-CELL DEFICIENT

JHD RECIPIENTS – B-CELL DEFICIENT.

RECIPIENT MICE EUTHANIZED

1,2,3 AND 4 WEEKS AFTER INFECTION;

INFECTED CONTROL MICE DIE

ABOUT 10 DAYS AFTER INFECTION.

McKinstry KK, Strutt TS, Kuang Y, Brown DB, Sell, S, Dutton RW and Swain SL. 2012. Memory

CD4+ T cells protect against influenza through multiple, synergizing mechanisms. J. Clin.

Invest. 122:2847-56. PMCID:PMC3408751

SCID

CD4 TX

SARS CoV-2 POTENTIAL IMMUNOGENS

T-CELL RESPONSE TO COVID-19 INFECTION

1. T-cells are selectively purified from blood and quantified

(NOTE. Specificity of antibodies used for cell isolation and characterization

of cell populations not described.)

2. COVID19 antigens are added to individual cultures

3. Activated T-cells produce INF-γ

4. INF- γ identified by immune labeling as a spot

5. Each spot corespondes to COVID-19 antigen footprint of

an individual activated T-cell

T-SPOT®Discovery SARS-CoV-2 kits

(Oxford Immunotec Ltd),

1.Begin with whole blood sample

2.Buffer and antibodies are added. Antibodies bind to mononuclear immune cells

3.Bead reagent added. Beads form antibody-mediated complexes with the

mononuclear immune cells (T-cell, B-cells, NK cells, monocytes)

4.Magnet is applied to sample to attract bead-complexed cells. Magnet is then

removed from sample, extracting the mononuclear immune cells

5.Mononuclear immune cells are washed whilst remaining attached to the magnet

6.Magnet is removed and mononuclear cells are resuspended in a new tube

we measured numbers of interferon-γ secreting, SARS-CoV-2 responsive T

cells using T-SPOT®Discovery SARS-CoV-2 kits (Oxford Immunotec Ltd),

T cells responsive to the spike (S), nuclear (N) and membrane proteins (M)

dominated the responses measured. Using the sum of the spots (responsive

cells within each well of 250,000 peripheral blood mononuclear cells) for S, N

and M antigens minus the control, the 2,672 unselected participants were

divided into those with higher responses (n=669, 25.4%; median 30 spots (IQR

18,54)) and those with low responses (n=2016, 76.7%, median 3 (IQR 1,6)), the

cutoff we derived being 12 spots. Of the participants with higher T cell

responses, 367 (53%) had detectable antibodies against the N or S proteins.

During a median of 118 days follow-up, 20 participants

with lower T cell responses developed COVID-19,

compared with none in the population with high T cell

responses (log-rank test, p=6×10−3

).

Wyllie, D, et al. SARS-COVID responsive T-cell numbers are associated with protection

from COVID-19: A prospective cohort study in keyworkers. medRxiv

PRELIMINARY REPORT. NOT PEER REVIEWED

GRAFT VS HOST SKIN LESIONS

GRAFT VS HOST DISEASE

SKIN GRAFT REJECTION

LYMPHOCYTE INFILTRATE IN SKIN GRAFT REJECTION

SKIN GRAFT

REJECTION

IN MICE

NORMAL KIDNEY RENAL GRAFT REJECTION

200x

100x

400x

RENAL GRAFT REJECTIONNORMAL

RENAL GRAFT REJECTION – CELL MEDIATED

MACROPHAGES

CYTOTOXIC

T-CELLS

LYMPHOCYTES

PLASMA CELLS

RENAL TUBULE

STAGES OF RENAL GRAFT REJECTION

A. HYPERACUTE PREFORMED AB

B. ACUTE CELLULAR

C. CHRONIC

ANTIBODY AND CELL MEDIATED

ARTERIES LIKE CHRONIC

POLYARTERITIS NODOSA A

CB

From: Sell S. Immunology, Immunopathology and Immunity. 6th Edition; ASM press, 2001

CD4 AND CD8 KILLER CELLS

1912

HASHIMOTO’S THYROIDITIS

HASHIMOTO’S THYROIDITIS

THYROIDITIS GRAVES DISEASE

PSORIASIS

VALORTIM RAXIBACUMAB ANTHRAX

SYNAGIS PALIVZUMAB RESPIRATORY SYNCYTIAL VIRUS

mAb-114 , Z-Mapp, RABIES

REGN-COV2 2 MONOCLONALS SARS2 CORONAVIRUS

UNDER DEVELOPMENT HIV

UNDER DEVELOPMENT SNAKE VENOM

HUMIRA ADALIMUMAB RHEUMATOID ARTH, PSORIASIS

BENLYSTRA BELIMUAB SLE

RITUXAN RITUXIMAB SCLERODERMA

XOLAIR OMALIZUMAB ASTHMA

MEPOLIZUMZB RESILIZUMAB ASTHMA

FASENRA BENRALIZUMAB EOSINOPHILIC ASTHMA

DUPIXENT DUPILUMAB ATOPIC ECZEMA

ORTHOCLONE-Okt3 MUROMONAB-CD3 KIDNEY GRAFT REJECTION

SIMULECT BESILIXIMAB KIDNEY GRAFT REJECTION

TALZ IXCKIZUMAB PSORIASIS

CONSNTEX SECUKINUMAB PSORIASIS

SKYRIZA TILDRAKIZUMAB PSORIASIA

TREMFYA GUSELKUMAB PSORIASIS

RAPTIVA EFALIZUMAB ALOPECIA

REMICADE INFLIXIMAB CROHN DISEASE

ENTYVIO VEDOLIZUMAB CROHN DISEASE

STELARA USTEKINUMAB PSORIASIS, CROHN

ANTI-CTLA-4 IPILUMAB CANCER

PROLIA DENOSUMAB OSTEOPOROSIS

SOME HUMANIZED MONOCLONAL ANTIBODIES USED IN THERAPY

HUMIRA ADALIMUMAB ANTI-TNF

TNF (TUMOR NECROSIS FACTOR, CACHEXIN) CELL SIGNALLING

CYTOKINE FEVER, APOPTOTSIS AND INFLAMMATION

HUMIRA TREATMENT OF PLAQUE PSORIASIS – 16 WEEKS

PGA – PHYSICIAN GLOBAL ASSESSSMENT – INCLUDES SYMPTOMS (DEPRESSION, ETC.)

PASI – PSORIASIS AREA AND SEVERITY INDEX

TREMFYA GUSELKUMAB ANTI-IL-23

SKYRIZA GUSELKUMAB

TALTZ IXCKIZUMAB

CONSENTYX SECUKINUMAB ANTI- IL-17

HUMIRA ADALIMUMAB AbbVie, Inc ANTI-TNF

INFLIXIMAB Johnson & Johnson

IL-23 MADE BY MACROPHAGES

INDUCES EXRESSION OF IL-17 AND TNF

IL-17 INDUCES CHEMOKINES

THAT ATTRACT AND

ACTIVATE IMACROPHAGES

AND NEUTROPHILS

INDUCES KERATINOCYTE

EXPRESSION OF CXCL1 AND CXCL8

WHICH ATTRACT T-CELLS

TNF (CACHEXIN)

CYTOKINE

FEVER

APOPTOTSIS

INFLAMMATION

IL-17

COSENTYX PSORISIS

Alopecia

RUXOLITINIB, TOFADFNIB

Samll molecular inhibitors of JAK1 and JAK2

NORMAL LIVER CHRONIC ACTIVE HEPATITIS

CHRONIC ACTIVE HEPATITIS

T-CELL CYTOTOXICITY

POSTULATED TREATMENTS FOR CHRONIC ACTIVE HEPATITIS

HEPATITIS VACCINE T-CTLHEPATITIS VACCINES

CD4 CTLs AND ANTIBODY

CRHON’S DISEASE