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- State of unresponsiveness to antigens (self Ags especially)
- Central tolerance: Central thymic tolerance to self antigens (autoantigens)
- Peripheral tolerance in lymphoid organs:
- 1. Self-reactive T cells ignore self-antigens (sequestered from circulation)
- 2. Self antigens present in privileged sites ignored
- 3. Self-reactive T & B cells deleted
- 4. Self-reactive T cells rendered anergic (unresponsive)
- 5. Self antigens kept in check by T regulatory cells
- Failure of self-tolerance leads to autoimmunity: The immune system attacks the body’s own cells and tissues
- Gene rearrangements (such as VDJ recombinations) in the central lymphoid organs (e.g. thymus & BM) inevitably generate lymphocytes that have affinity for self-antigens. These are normally removed or kept in check by self-tolerance, in which an individual’s immune system does not attack the normal tissues of the body.
- Failure of tolerance mechanisms leads to autoimmunity
Role of Autoimmune regulator (AIRE) gene in thymic tolerance
- - Aire gene in the thymic medulla turns on ectopic (outside) expression of self Ag, peptides to be tested against thymocyte being presented by MHC
- - Tolerance through anergy or deletion. The ones fail the test, either don't bind, or bind too vigorously, are removed. Positive/negative selection
Layers of self-tolerance - mechanism @ site of action
- central tolerance - deletion (apoptosis), editing (receptor; B cells), development of Treg @ thymus, BM
- Ag segregation - physical barrier to self-Ag access to lymphoid system @ peripheral organs (e.g. thyroid, pancreas)
- Peripheral anergy - cellular inactivation by weak signaling w/o costimulus @ secondary lymphoid tissue
- Regulatory cells - suppression by cytokines, intercellular signals @ secondary lymphoid tissue and sites of inflammation
- Cytokine deviation - differentiation to TH2 cells, limiting inflammatory cytokine secretion @ secondary lymphoid tissue and sites of inflammation
- Clonal deletion - apoptosis post-activation @ secondary lymphoid tissue and sites of inflammation
Fates of lymphocytes after encounter of antigens
- Normal immune response to pathogenic Ag - proliferation and differentiation
- Self-tolerance to self Ag - Anergy (unresponsive); Deletion (cell death); Change in specificity (receptor editing)
Mechanisms of T cell anergy
- In normal responses: recognition of foreign antigen with costimulation by T cell and APC expressing costimulators, activation, effector T cell proliferation and differentiation.
- In T cell anergy: recognition of self Ag leads to either signaling block (costimulator lacking) or engagement of inhibitory receptors (e.g. CTLA-4), resulting in unresponsive T cell (anergic)
The correlation between avidity and thymocyte selection
- avidity too low: apoptosis
- avidity intermediate: positive selection; at the highest end is the selection of CD25+ Treg
- avidity high: negative selection; apoptosis
Treg cells (FoxP3+, CD4+, CD25+; TGF-β, IL-10)
- moderately autoreactive that escaped deletion in the thymus
- When activated by self antigen, they cannot initiate an autoimmune response; instead, they differentiate into powerful suppressor cells that inhibit other selfreactive T cells that recognize Ags on the same tissue
- Therapeutic intervention of colitis (inflammation of the colon), diabetes, SLE (EAE in mouse model)
Self Ag-induced death of peripheral T lymphocytes
- Normal immune response: expression of anti-apoptotic (survival) proteins, induced by IL-2 (T cell growth factor), which is released by activated T cell -> T cell proliferation and differentiation
- Self Ag recognifition: induction of pro-apoptotic proteins (e.g. Bim) -> apoptosis
- Self Ag recognifition: expression and engagement of death receptors, Fas:FasL -> apoptosis
Role of regulatory T cells in T cell-mediated suppression
- Differentiated in thymus (main site) and lymph node w/ the help of IL-2 when avidity is medium high.
- Inhibit peripheral (self-Ag responsive) T cell activation or function via TGF-beta.
Central deletion or inactivation of newly formed lymphocytes is the first check point of self-tolerance
- 1. Organs express tissue-specific Ags
- 2. In thymus, T cells recognizing those Ags arise
- 3. Under control of AIRE protein, thymic medullary cells express tissue-specific proteins, deleting tissue-reactive T cells.
- 4. In the absence of AIRE, T cells reactive to tissue-specific Ags mature and leave thymus
- - AIRE (auto-immune regulator) gene promotes expression of many tissue-specific antigens in the thymic medullar cells.
- - Rare inherited deficiency of AIRE leads to APECED (auto-immune polyendocrinopathy-candidiasis-ectodermal dystrophy) – autoimmune destruction of multiple endocrine tissues, such as insulin producing pancreatic cells
Self Ags recognized by TLRs can ___________.
- activate autoreactive B cells by providing co-stimulation
- B cells w/ specificity for DNA bind soluble fragments of DNA, sending a signal through BCR
- The cross-linked B-cell receptor is internalized w/ bound DNA
- GC-rich fragments of the internalized DNA bind to TLR-9 in an endosomal compartment, sending a co-stimulatory signal
- - Unmethylated CpG DNA (common in bacteria) is produced in mammalian cells undergoing apoptosis (possibly as result of infection)
Factors that Determine the Tolerogenicity of Self Ags: favoring immune response vs favoring tolerance
- - optimal doses vs. high doses
- - short-lived vs. prolonged
- - subcu, intradermal, absence from generative organs vs. intravenous, oral, presence in generative organs
- - Ag w/ adjuvants (stim TH cells) vs. Ag w/o adjuvants
- - APC w/ high levels of costimulators vs. APC w/ low levels of costimulators and cytokines
Immunologic privileged sites
- Uterus (fetus)
- Hamster cheek pouch
- - Tissue grafts placed in these sites often last indefinitely
- - The Ags sequestered at these sites are often targets of autoimmune attack.
Infectious agents could break self tolerance in different ways
- Disruption of barrier - release sequestered self Ag; activate nontolerized cells. E.g. sympathetic ophthalmia
- Molecular mimicry - produce cross-reactive Ab or T cells. E.g. rheumatic fever, reactive arthritis, lyme arthritis
Damage to immunologically privileged site can induce autoimmunity
- Trauma to one eye releases sequested intraocular protein Ags
- Released Ags are carried to lymph nodes and activate T cells
- Effector T cells return via bloodstream and encounter Ag in both eyes - sympathetic ophthalmia
Tolerance mediated by regulatory T cells can inhibit multiple autoreactive T cells that all recognize the same tissue
- T-cell specific for self Ag in thymus becomes a natural Treg
- T cell in peripheral specifc for self or commensal microbiota Ag recognized in presence of TGF-beta becomes an induced Treg
- IL-10 and TGF-beta released by Treg inhibit other self-reactive T cells in periphery
- The response of the immune system against the body’s own tissues (i.e. response to self). This often leads to Autoimmune Disease
- - “Horror autotoxicus” – Paul Ehlich (“The Body turns against itself”)
- Autoantigens: are self molecules recognized as Ags
- Autoantibodies: are Abs that react against self Ags
- Autoreactive cells: are lymphocytes with receptors for self Ags
Why does autoimmunity develop?
- Failed central tolerance
- - Flawed thymic selection
- - Failure in deletion of autorective lymphocytes
- - Failure in activation-induced cell death (AICD)
- Defects in peripheral tolerance
- - Hyper-immune stimulation (e.g. unregulated costimulation)
- - Cytokine imbalance
- - T cell bypass: Most self-reactive T cells are deleted or anergized, but autoreactive B cells may become activated by a mechanism that bypasses the tolerant T cell. A cross-reactive exogenous Ag taken up by an autoreactive B cell could be presented to a T cell recognizing a non-self epitope, which then helps the B cell.
Requirements for development of autoimmune disease
- Failure of intrinsic tolerance mechanisms and/or environmental triggers such as infection, may lead to autoimmunity in genetically predisposed individuals.
- Genetic factors and infection & environmental exposure act together on immune regulation -> autoimmunity
Autoimmune diseases may be classified as organ-specific or non-organ-specific depending on whether the response is primarily against antigens localized to particular organs or against widespread antigens.
Not all autoimmune diseases fit the classification - autoimmune hemolytic anemia can occur in isolation or with SLE.
Organ specific autoimmune disease
- M.S. - CNS, myelin
- Goodpasture's syndrome - lungs and kidneys; collagen IV
- insulin-dependent diabetes mellitus - pancreatic beta cells
- Crohn's disease - Mucosa (GI, mouth, anus) - NOD2 (non-obese diabetes II; F=M)
- Psoriasis - skin plaques, discolored nails
- Graves’ disease - anti-TSHR-hyperthyroidism
- Hasimoto thyroiditis - Thyroid gland-hypothyroidism
- Autoimmune hemolytic anemia - RBC destruction
- Autoimmune Addison's disease - Adrenal insufficiency
- Vitiligo - skin depigmentation; melanocyte death
- Myasthenia gravis - muscle; Ach receptors
Non-organ-specific (systemic) autoimmune disease
- Rheumatoid arthritis (RA) - IgM anti-IgG (RF in joints)
- Scleroderma - arteriole hardening (ANAs -skin, heart, kidney, lung)
- SLE - various tissues (skin, heart, lung, kidney, intestine, CNS)
- Primary Sjogren's syndrome - anti-nuclear Abs, anti-Ach receptor Abs, dry mouth
- Polymyositis - inflammation of muscle fibers
Anti-IgG Abs produced to immune complex of IgG, as a result of infection. These are usually of IgM isotype, and are normally short-lived, and are cleared, but become immunogenic if uncleared. E.g. Rheumatoid arthritis
_________ in germinal centers can produce self-reactive B cells. These are normally removed by _______.
- Somatic hypermutation
Sex difference of autoimmune diseases
- Many are more common in females than males
- frequently X-linked
- double dosage
Inflammatory bowel disease and colitis
- - result from autoreactive T cells in the lamina propria
- - Can be treated by transfer of CD4 CD25 Treg cells, which home to the colon and mesenteric lymph nodes
- - They proliferate and inhibit the pathogenic effector T cells
- - After inflammation resolves, CD4 CD25 Treg cells remain in clusters w/ DC and pathogenic effector T cells
- Auto-Abs inhibit receptor function
- Ach receptors are internalized and degraded
- Ab-mediated autoimmune diseases; can appear in the infants of affected mothers as a consequence of transplacental anti-TSHR Ab (IgG) xxtransfer
- plasmapheresis removes maternal anti-TSHR Ab and cures the disease in newborn.
Experimental Allergic Encephalomyelitis (EAE) mouse model for ___________.
Pathogenesis of multiple sclerosis
- - Unknown trigger sets up initial focus of inflammation in brain and blood-brain barrier becomes locally permeable to leukocytes and blood proteins
- - T cells specific for CNS Ag and activated in peripheral lymphoid tissues reencounter Ag presented on microglia or DC in brain
- - Inflammatory reaction in brain due to mast-cell activation, complement activation, Ab, and cytokines
- - Demyelination of neurons
T cells specific for ________ mediate ________ of the brain in experimental autoimmune encephalomyelitis (EAE).
- myelin basic protein
- - Mice injected w/ myelin basic protein and complete Freund's adjuvant develop EAE and are paralyzed
- - The disease is mediated by TH1 specific cells (IFN-gamma and TFN-a released) for myelin basic protein
- - disease can be transmitted by transfer of T cells from affected animal
Autoimmune hemolytic anemia
- - RBCs coated with IgG auto-Abs are readily cleared by FcR+ macrophages; RBCs coated with IgM auto-Abs fix C3 and are cleared by CR1+ and C3+ macrophages. Both mainly occur in the spleen
- - Binding of rare auto-Abs that fix complement avidly cause formation of membrane-attack complex, resulting in intravascular hemolysis
- - An autoimmune disease characterized by inflammation of the glands of the eyes and mouth (lachrymal and salivary), which can lead to severe eye and mouth dryness
- - 9-10x more in women; usually in late 40s
- - Can occur alone (primary Sjogren's syndrome) or later in association with rheumatoid arthritis, SLE, scleroderma, primary biliary cirrhosis, etc. (Secondary Sjögren's syndrome).
- - Characterized by presence of anti-nuclear Ab (ANA; directed against contents of the cell nucleus) and rheumatoid factor in serum. The rheumatoid factor is usually antibody against the Fc portion of IgG.
Autoantibodies in Sjogren’s syndrome
- Anti-nuclear antibodies:
- - Anti-Ro/SSA- Most prevalent (e.g. SLE, SLE/SS); 52 & 60 kD protein + small RNA particles
- - Anti-LA/SSB- more associated with SS; 48-52 kD protein + small RNA particles
- Rheumatoid factors
- - IgM anti-IgG Fc (30% rheumatoid arthritis patients do not have RF)
- - IgA RF in pSS
- Anti-M3, acetylcholine (muscarinic) receptor
Immunologic cascade in Sjogren's syndrome pathogenesis
- - Genes and environment produce auto Ags, carried by DCs, go to lymph nodes and spleen
- - Ags go into glands, complements are produced and inflammation starts
- - Chemokine, CXCL13 is produced and is a chemoattractant for B and T cell, go from lymph nodes into glands, then initiate ectopic germinal centers and reaction occurs in the glands
- - These cells are vigorously reactive can get out and cause lymphoma
Transfer of Autoantibodies to infants
- Mother with SLE or Sjogren’s syndrome
- Placental transmission of IgG autoantibodies
- Failure of infant to catabolize autoantibodies early leads to Chronic organ damage of infant – heart
Animal models of Sjogren’s syndrome
- Ovariectomized Non-obese diabetic (NOD) mice
- Increased cytokine/chemokine secretion in lacrimal glands - IL-1, TNF-α, IL-17, CXCL13
- Damage to lacrimal gland like in human SS
Autoimmune diseases transferred across the placenta to the fetus and newborn infant
- Myasthenia gravis: Anti-acetylcholine receptor -> Muscle weakness
- Graves' disease: Anti-thyroid-stimulating-hormone (TSH) receptor -> Hyperthyroidism
- Thrombocytopenic purpura: Anti-platelet antibodies -> Bruising and hemorrhage
- Neonatal lupus rash and/or congenital heart block: Anti-Ro/La antibodies -> Photosensitive rash and/or bradycardia
- Pemphigus vulgaris: Anti-desmoglein-3 -> Blistering rash
Autoimmune diseases involve all aspects of the immune response
- SLE: T - pathogenic or help for Ab; B - AP to T; Ab - pathogenic
- Type 1 diabetes: T - pathogenic; B - AP to T; Ab - unclear
- Myasthenia gravis: T - help for Ab; B - Ab secretion; Ab - pathogenic
- M.S.: T - pathogenic; B - AP to T; Ab - unclear
- Graves' disease -> TSHR
- Myasthenia gravis -> AchR
- Insulin-resistant diabetes (2) -> insulin receptor (antagonist)
- Hypoglycemia -> insulin receptor (agonist)
- Chronic utricaria -> receptor-bound IgE or IgE receptor (agonist)
Therapeutic Management of autoimmune Diseases
- - Anti-inflammatory drugs - corticosteroids
- - Antagonists to pro-inflammatory cytokines and their receptors
- - Antagonists to costimulatory molecules – CTLA4-hIg blocks B7
- - Plasmapheresis -> Ab IgG
- - Ab-dependent cell-mediated cytotoxicity (ADCC): Anti-CD20 mAb (with human Fc), anti-CD40 mAb
- - Intravenous IgG
The process of taking cells, tissues, or organs, called a graft, from one individual and placing them into a (usually) different individual
graft transplanted from one site to another in the same individual. eg. skin grafts – autologous graft
Isograft (syngraft) /syngeneic transplantation
graft transplanted between two genetically identical or syngeneic individuals, i.e. identical (homozygotic) twins
graft transplanted between two genetically different individuals of the same species– most common type of graft
molecules that are recognized by T cells as foreign on allografts
Orthotopic (homotopic) transplantation
The graft is placed into its normal anatomic location
transplantation of tissue typical of one area to a different site in a recipient.
between members of different species
Transplantation and Rejection
- The barrier to transplantation is the genetic disparity between donor and recipient.
- The immune response in transplantation depends on a variety of factors:
- - Host versus graft responses cause transplant rejection.
- - Histocompatibility Ags are the targets for rejection.
- - Minor Ags can be targets of rejection even when donor and recipient MHC are identical.
- - Graft versus host reactions result when donor lymphocytes attack the graft recipient (i.e. host).
- Rejection results from a variety of different immune effector mechanisms:
- - Hyperacute rejection is immediate and caused by antibody.
- - Acute rejection occurs days to weeks after transplantation
- - Chronic rejection is seen months or years after transplantation.
Testing for donor-recipient compatibility in transplantation
- ABO matching
- HLA matching: HLA-A, HLA-B, HLA-DR
- Preformed Abs
- Cross matching - see if the Abs recognize
The initiation of graft rejection normally involves the migration of donor APC from the graft to local lymph nodes, activation of effector T cells, and T cells' migration back to graft via blood to destroy graft.
- Depletion of passenger leukocytes extends grafting
- If site of grafting lacks lymphatic drainage, no response to graft occurs.
Skin graft rejection is the result of T cell-mediated anti-graft response
- Syngeneic -> same MHC, tolerated
- Allogeneic -> different MHC, rejected
- For naive recipient, rejection happens quickly
- For second-time recipient (same host/donor), rejection happens even faster
- For naive host, if T cell from sensitized host is injected, rejection happens as faster as second-time receiver
Even complete matching at the MHC locus does not ensure graft survival
if the minor H antigen is incompatible
Minor H antigens are peptides derived from polymorphic cellular proteins bound to MHC class I molecules
- polymorphic self proteins that differ in AA sequence between individuals give rise to minor H Ag differences between donor and recipient
- TAP (transporters associated with antigen processing) is involved in taking the peptide into ER before it is attached to MHC and presented on cell surface.
- Targeted by CD8 T cells
Alloantigens in grafted organs are recognized in two different ways
- Direct recognition - Donor APCs migrate to secondary lymphoid tissue (LN or spleen) and stim alloreactive recipient T cells
- Indirect recognition - Recipient APCs process proteins and present peptides derived from the graft
Preexisting Ab against donor graft Ags (e.g. blood group antigens) can cause _______ rejection within _____.
- preexisting Ab bind vascular endothlium of graft, initiating inflammation, occluding blood vessels, killing the graft.
Among commonly transplanted organs, _____ has the highest 5-yr survival rate, _____ is most frequently transplanted.
- circulating allo-Ag specific Ab binding, complement activation, endothelial damage, inflammation and thrombosis.
- - Minutes after transplant
- - Ab & C’
- - Typical in ABO incompatibility & xenografts
- parenchymal cell damage, interstitial inflammation, endothelialitis
- - Days to weeks after transplant
- - Alloreactive CD8 CTL
- - CD4 T cell cytokines recruit inflammatory cells: DTH (Delayed type hypersensitivity)-like
- chronic DTH in vessel wall, intimal smooth muscle cell proliferation, vessel occlusion
- - Months to years after transplant
- - accelerated arteriosclerosis
- - Specialized DTH – lymphocytes induce macrophages to secrete smooth muscle growth factors
Mixed lymphocyte reaction (MLR) used for detection of histocompatibility
- - Lymphocytes from two individuals to be tested for compatibility are isolated from peripheral blood and mixed.
- - Stimiulator cells - including APCs; from one person, either irradiated or treated with mitomycin C, can't respond by DNA synthesis and cell division to antigenic stimulation
- - Responders cells, the unirradiated lymphocytes, if contain alloreactive T cells, will be stimulated to proliferate and differentiate to effector cells between 3 and 7 days after mixing.
- - Assessed for T-cell (CD4) proliferation, recognizing differences in MHC class II molecules, measuring H3-thymidine incorporated in DNA.
- - Or assessed for the generation of activated cytotoxic T cells (51Cr-labeled), responding to differences in MHC class I molecules.
Structures of the ABO blood group antigens
- - All have a common structure: ceramide, Glu, Gal, GalNac, Gal, Fuc
- - A antigen: extra GalNAc
- - B antigen: extra Gal
Donors and recipients for blood transfusion must be matched for the ABO system of blood group antigens
- A: RBC has A-Ag, plasma contains Anti-B Ab -> A, AB
- B: B-Ag, Anti-A Ab -> B, AB
- O: Anti-A and B Abs -> A, B, AB, O
- AB: A- and B-Ags, no Ab against A or B -> AB
Matching the ABO and rhesus erythrocyte antigens in blood transfusion
- A/B/AB/O - RhD+/-
- blood type w/ highest frequency in US population is O+ and A+
- AB- being the lowest
Graft-versus-host Disease, GVHD (converse of graft rejection)
- - Major complication of allogeneic bone marrow transplantation:
- - Donor T cells recognize host tissues as foreign, causing severe inflammatory disease.
- - Particularly violent when there is mismatch of MHC class I and II Ags
- - Occurs even in disparities in minor histocompatibility Ags.
- - Occurs if the host is severly immunocompromised and cannot reject the alloreactive T cells
- - Sometimes seen in solid organ transplants such as lung or small bowel
- - Classified into Acute or Chronic GvHD
Recipient type APCs are required for the efficient initiation of GVHD
- Donor T cells can recognize minor histocompatibility Ags of the recipient and start an immune response against the recipient's tissues.
- In stem-cell transplantation, minor Ags could be presented by either recipient- or donor-derived APCs.
- Cross-presentation of the recipient's minor histocompatibility Ags on donor APCs is not sufficient to stimulate GVHD; Ags endogenously synthesized and presented by the recipient's APCs are required.
- Mice w/ host APCs knocked out were entirely resistant to GVHD mediated by donor CD8 T cells.
BONE MARROW TRANSPLANTATION
- Pluripotent hematopoietic stem cell (CD34+) of donor - cord or peripheral blood; donor cells mobilized into circulation by treatment with GM-CSF
- Since allogeneic stem cells are readily rejected by minimally immunocompetent host, host immune system is ablated by radiation and chemotherapy prior to transplantation.
- Used to treat hematological malignancies, anemias, immune deficiency disorders and some solid tumors.
- In addition to alloreative T cells, NK cells also play a role in BM rejection
- GVHD is common in BM transplants and the principal limitation to successful BM transplantation.
Alloreactions in transplant rejection and graft versus host reaction
- host T cell vs graft
- graft T cell vs recipient
Histopathology of acute GVHD in the skin
- Apoptotic cells seen
- Destruction due to apoptosis
Methods of Immunosuppression to prevent or treat allograft rejection
- Anti-CD3 monoclonal Ab: Depletes T cells (any type) by binding to CD3 and promoting phagocytosis or complement-mediated lysis (used to treat acute rejection)
- CTLA-4-Ig: Inhibits T cell activation by blocking B7 costimulator binding to T cell CD28; in clinical trials
- Anti-CD40 ligand: Inhibits macrophage and endothelial activation by blocking T cell CD40 ligand binding to CD40; in clinical trials
- Anti-IL-2 receptor (CD25) antibody: Inhibits T cell proliferation by blocking IL-2 binding and depletes activated T cells that express CD25
- Rapamycin: inhibiting IL-2 signaling (important to T activation) -| proliferation
- Azathioprine: Blocks proliferation of lymphocyte precursors
- Mycophenolate mofetil (MMF): inhibiting guanine nucleotide synthesis in lymphocytes -| proliferation
- Cyclosporine and FK-506: inhibiting activation of the NFAT transcription factor -| T cell cytokine production
- Corticosteroids: inhibiting macrophage cytokine secretion -| inflammation
Regulatory T cells in future GVHD therapy
- - Recipient CD4+CD25+ Treg cells activated and expanded ex vivo and injected into recipient prior to BM transplant
- - Recipient CD8+CD28- Treg cells, with anergic phenotype are thought to maintain T-cell tolerance by inhibiting the capacity of APCs to activate helper T cells
Setbacks to sustained immunosuppression
- • opportunistic viral infections with CMV and HSV
- • B cell lymphomas (EBV) and squamous cell carcinomas of the skin (HPV)
The fetus is an allograft that is not rejected (tolerance!) - Hypotheses:
- - Trophoblast (separates fetal and maternal tissues) does not express MHC class I or II. Vulnerable to attack by NK cells.
- - Protection from NK killing by expression of non-classical MHC class I (HLA-G) which binds the
- two major inhibitory NK receptors (KIR1 and KIR2), and prevents killing.
- - Uterine epithelium and trophoblast secrete TGF-β, IL-4, and IL-10 which suppresses TH1 response.
The favored animal for xenotransplantation is the pig
- - physiological and anatomical compatibility
- - ability to breed large numbers of animals rapidly
- Barriers :
- - public acceptability
- - safety (transmission of viruses from pigs- not major concern)
- - scientific issues - preventing graft rejection (genetically engineered/humanized pig)
Basic principles of tissue engineering
- take cells from a biopsy
- culture in the lab
- make a scaffold - artificial matrix w/ recipients cells or biological matrix from pigs
- generate a graft
- implant back to the person
Skin cell spray - transplantation device
culture stem cells w/ cytokines, GF, spray on to burn site