Cell-Mediated Immunity

CELL-MEDIATED IMMUNITY

T-CELL CYTOTOXICITY

DELAYED HYPERSENSITIVITY

GRANULOMATOUS REACTIONS EFFECTOR T-CELLS

LEVELS OF REACTIONS OF ANTIGEN WITH ANTIBODY OR CELLS

PRIMARY SECONDARY TERTIARY REACTION REACTION REACTION in vitro in vivo ANTIBODY MEDIATED INACTIVATION NEUTRALIZATION

AGGLUTINATION, LYSIS CYTOLYTIC REACTIONS OPSONIZATION Ag+Ab AgAb IMMUNE COMPLEX PRECIPITATION REACTIONS

MAST CELL ANAPHYLACTIC DEGRANULATION REACTIONS

CELL MEDIATED DELAYED T-DTH HYPERSENSITIVITY LYMPHOKINES REACTIONS +Ag-> MACROPHAGE ACTIVATION

BLAST CELL TRANSFORMATION T-CTL TARGET-CELL LYSIS DESTRUCTION

Ab or + INSOLUBLE ANTIGEN GRANULOMA TYPE I ANTIGENIC STIMULUS TYPE II CD4+ T-CELL Th1 – DIRECTED TO CELLULAR Th2 – VASCULAR EFFECTS RESPONSES, Antibody & CMI SECRETORY ANTIBODY

B- CELL B-CELL CD8+ INHIBITION Th17 IL-17 INF-γ Th1 T IL-4 IL-4, OF Il-13 Th2 -10, -13 INFLAM- INF-γ INF-γ MATION IL-17 TNF (M2 Mϕ) IgG1, IgG3 IL-5 COMPLEMENT FIXING CD4+ EOSINOPHILS ANTIBODIES T IgG2, IgG4 IgA ANTIBODY IgE CTL DIFFERENTIATION M1 MACROPHAGE NEUTRA- AND ACTIVATION ACTIVATION LIZATION OPSONIZATION, PHAGOCYTOSIS DELAYED MAST CELL HYPERSENSITIVITY DEGRANULATION T-CELL CYTOXICITY CONTACT 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

CONTACT DERMATITIS

NICKEL DERMATITIS

POISON OAK

NORMAL SKIN CONTACT DERMATITIS CONTACT DERMATITIS

INCREASED LYMPHOCYTES IN DERMIS

LYMPHOCYTES IN EPIDERMIS ALLERGIC CONTACT DERMATITIS

40X 200X

400X 400X

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 IMMUNOPATHOLOGY OF MURINE MODELS OF EXPERIMENTAL INFLUENZA

Stewart Sell Ian Guest Kai McKinstry Tara Strutt Jacob Kohlmeier Erik Brinks Wadsworth Wadsworth U. Massachusetts U. Massachusetts Emory U. U. Minnesota

David Woodward Richard Dutton Suzy Swain Mike Tighe Marcia A. Blackman U. Massachusetts Trudeau Institute Trudeau Institute Keystone Symposia 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 EXPERIMENTAL INFLUENZA INFECTION OF MOUSE LUNG

TYPE I PNEUMOCYTES

TERMINAL BRONCHIOLE TYPE II PNEUMOCYTES EPITHELIAL CELLS

IMMUNPEROXIDASE STAIN FOR VIRUS ANTI-FLU VIRUS

NAÏVE 200x NAÏVE 400x

MEMORY T 200x MEMORY T 400x NORMAL – NOT INFECTED FLU INFECTED – DAY 8

ARTERY

LYMPHOCYTES GOBLET CELLS

BASEMENT MEMBRANE

Br EXPERIMENT 3. TRANSPLANTATION OF CD4 MEMORY CELLS TO SCID MICE PARTIALLY PROTECTS.

ALSO NUDE AND JHD RECIPIENTS. CD4 TX 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. SCID

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 T-CELL RESPONSE TO COVID-19 INFECTION

SARS CoV-2 POTENTIAL IMMUNOGENS T-SPOT® Discovery SARS-CoV-2 kits (Oxford Immunotec Ltd),

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 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 NORMAL RENAL GRAFT REJECTION

100x

200x 400x RENAL GRAFT REJECTION – CELL MEDIATED

PLASMA CELLS

LYMPHOCYTES CYTOTOXIC T-CELLS

MACROPHAGES 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

B C

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

SOME HUMANIZED MONOCLONAL ANTIBODIES USED IN THERAPY 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 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 VACCIHEPATITISNE VACCINEST-CTL CD4 CTLs AND ANTIBODY CRHON’S DISEASE