Comparison of genetic and/or pharmacologic CTLA-4 loss in humans and mice
| Disease feature | Human | Mouse | |||
|---|---|---|---|---|---|
| CTLA4−/− | CTLA4+/− | Ipilimumab-treated | Ctla4−/− | Ctla4+/− | |
| Genetic variant | Homozygous Ser172Pro (hypomorphic, n = 1) | Heterozygous loss-of-function | Not applicable | Homozygous loss-of-function | Heterozygous loss-of-function |
| Outcome | Alive at 9 years old on abatacept, immunoglobulin replacement, and prophylactic antibiotics | Variable disease penetrance (∼70% affected). Most respond to sirolimus or abatacept and replacement immunoglobulin if needed. Hematopoietic stem cell transplantation is an option for severe cases | Immune-related adverse effects appear within a few weeks to months after treatment. Most resolve upon delaying dose or with immunosuppressants | Death by ∼3–7 wk of age | Not reported (healthy) |
| Lymphoproliferation | Hepatosplenomegaly | Lymphadenopathy, hepatosplenomegaly | None | Hepatosplenomegaly | None (healthy) |
| Lymphocytic infiltration | Enteropathy (celiac disease) | Enteropathy, inflammatory bowel disease, granulomatous-lymphocytic interstitial lung disease, lymphocytic infiltrations in the brain, bone marrow, kidney, atopic dermatitis, and arthritis > pancreas | Dermatitis, enterocolitis, hepatitis, and pneumonitis | Multiorgan mononuclear infiltrates in heart (with cardiomegaly), pancreas, lungs, salivary glands, liver, bone marrow > synovium, and blood vessels | None (healthy) |
| | | | Increased activated T cells in spleen, lymph nodes, thymus, and increased activated B cells in spleen and lymph nodes | | |
| Autoimmunity | Immune thrombocytopenic purpura | Immune thrombocytopenic purpura, autoimmune hemolytic anemia, autoimmune neutropenia, thyroiditis/hypothyroidism, type 1 diabetes mellitus, psoriasis, vitiligo, and alopecia | Hypophysitis with pituitary autoantibodies, thyroiditis/hypothyroidism, and rarely autoimmune cytopenias | Anti-insulin, gastric parietal, Ro52, and dsDNA autoantibodies (when Ctla4 is conditionally deleted in Treg) | None (healthy) |
| | | | Worsened collagen-induced arthritis disease, but delayed or ameliorated experimental allergic encephalitis (when Ctla4 is conditionally deleted in Treg) | | |
| Infection susceptibility | Mild recurrent upper respiratory tract infections | Recurrent sinopulmonary (±bronchiectasis) and otitis media infections | Infrequent | None reported | None (healthy) |
| | Elevated EBV DNA copy number (while on methylprednisolone, azathioprine) | | | | |
| Other | | Lymphoma, gastric cancer | | | |
| Laboratory abnormalities | Increased circulating Tfh, effector memory and exhausted T cells | Normal or low numbers of total lymphocytes, T cells, CD4+ T cells, CD8+ T cells, Treg, B cells, and NK cells | Not investigated/reported | Spontaneous and TCR-stimulated proliferation and cytokine production | Increased germinal centers after immunization |
| Increased IFN-γ and IL-10 expression in T cells | Decreased numbers of Treg having impaired suppressor function, naïve T cells, and memory B cells | | Increased IFN-γ, IL-4, and GM-CSF upon TCR stimulation | | |
| Increased activated and atypical memory B cells | Increased numbers of activated memory T cells and circulating TFH cells | Increased Treg, Tfh, and Tfr (but Tfr are functionally impaired) | |||
| Hypogammaglobulinemia, poor vaccine titers | Hypogammaglobulinemia, poor vaccine titers | Hypergammaglobulinemia | |||
| References | This article in JHI (1) | (2, 3, 4, 5) | (2) | (6, 7, 8) | (7, 9) |
| Disease feature | Human | Mouse | |||
|---|---|---|---|---|---|
| Ipilimumab-treated | |||||
| Genetic variant | Homozygous Ser172Pro (hypomorphic, | Heterozygous loss-of-function | Not applicable | Homozygous loss-of-function | Heterozygous loss-of-function |
| Outcome | Alive at 9 years old on abatacept, immunoglobulin replacement, and prophylactic antibiotics | Variable disease penetrance (∼70% affected). Most respond to sirolimus or abatacept and replacement immunoglobulin if needed. Hematopoietic stem cell transplantation is an option for severe cases | Immune-related adverse effects appear within a few weeks to months after treatment. Most resolve upon delaying dose or with immunosuppressants | Death by ∼3–7 wk of age | Not reported (healthy) |
| Lymphoproliferation | Hepatosplenomegaly | Lymphadenopathy, hepatosplenomegaly | None | Hepatosplenomegaly | None (healthy) |
| Lymphocytic infiltration | Enteropathy (celiac disease) | Enteropathy, inflammatory bowel disease, granulomatous-lymphocytic interstitial lung disease, lymphocytic infiltrations in the brain, bone marrow, kidney, atopic dermatitis, and arthritis > pancreas | Dermatitis, enterocolitis, hepatitis, and pneumonitis | Multiorgan mononuclear infiltrates in heart (with cardiomegaly), pancreas, lungs, salivary glands, liver, bone marrow > synovium, and blood vessels | None (healthy) |
| | | | Increased activated T cells in spleen, lymph nodes, thymus, and increased activated B cells in spleen and lymph nodes | | |
| Autoimmunity | Immune thrombocytopenic purpura | Immune thrombocytopenic purpura, autoimmune hemolytic anemia, autoimmune neutropenia, thyroiditis/hypothyroidism, type 1 diabetes mellitus, psoriasis, vitiligo, and alopecia | Hypophysitis with pituitary autoantibodies, thyroiditis/hypothyroidism, and rarely autoimmune cytopenias | Anti-insulin, gastric parietal, Ro52, and dsDNA autoantibodies (when Ctla4 is conditionally deleted in Treg) | None (healthy) |
| | | | Worsened collagen-induced arthritis disease, but delayed or ameliorated experimental allergic encephalitis (when Ctla4 is conditionally deleted in Treg) | | |
| Infection susceptibility | Mild recurrent upper respiratory tract infections | Recurrent sinopulmonary (±bronchiectasis) and otitis media infections | Infrequent | None reported | None (healthy) |
| | Elevated EBV DNA copy number (while on methylprednisolone, azathioprine) | | | | |
| Other | | Lymphoma, gastric cancer | | | |
| Laboratory abnormalities | Increased circulating Tfh, effector memory and exhausted T cells | Normal or low numbers of total lymphocytes, T cells, CD4+ T cells, CD8+ T cells, Treg, B cells, and NK cells | Not investigated/reported | Spontaneous and TCR-stimulated proliferation and cytokine production | Increased germinal centers after immunization |
| Increased IFN-γ and IL-10 expression in T cells | Decreased numbers of Treg having impaired suppressor function, naïve T cells, and memory B cells | | Increased IFN-γ, IL-4, and GM-CSF upon TCR stimulation | | |
| Increased activated and atypical memory B cells | Increased numbers of activated memory T cells and circulating TFH cells | Increased Treg, Tfh, and Tfr (but Tfr are functionally impaired) | |||
| Hypogammaglobulinemia, poor vaccine titers | Hypogammaglobulinemia, poor vaccine titers | Hypergammaglobulinemia | |||
| References | This article in | ( | ( | ( | ( |
Sharing content requires targeting cookies to be enabled. Please update your cookie preferences to use this feature.